chr17-31214524-A-G

Position:

chr17-31214524-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP2PP5_Very_Strong

The NM_001042492.3(NF1):c.1466A>G(p.Tyr489Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,611,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:32

Conservation

PhyloP100: 6.75

Variant links:

Genes affected

NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

NF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 19) in uniprot entity NF1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001042492.3

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

PP5

Variant 17-31214524-A-G is Pathogenic according to our data. Variant chr17-31214524-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31214524-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.1466A>G	p.Tyr489Cys	missense_variant	13/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 linkuse as main transcript	c.1466A>G	p.Tyr489Cys	missense_variant	13/57		NP_000258.1	P21359-2
NF1	NM_001128147.3 linkuse as main transcript	c.1466A>G	p.Tyr489Cys	missense_variant	13/15		NP_001121619.1	P21359-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.1466A>G	p.Tyr489Cys	missense_variant	13/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250646

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135576

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1459782

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000843

Hom.:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:17

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 27, 2021	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP2 supporting, PP4 supporting -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Aug 01, 2017	NF1 NM_001042492.2 exon1 p.Tyr489Cys (c.1466A>G): This variant has been reported in >10 individuals with Neurofibromatosis type 1 (NF1), including 1 individual in which this variant was de novo (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084, Bongiomo 2008 PMID:19076627, Laycock-van Spyk 2011 PMID:22155606, Ribeiro 2012 PMID:22190595, Laurito 2015 PMID:25919870, Zhang 2015 PMID:26056819). This variant segregated with disease in 2 affected family members (Ars 2000 PMID:10607834). This variant is present in 3/245628 individuals of different ethnicities in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs137854557). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:354). Evolutionary conservation and computational predictive tools for this variant are unclear. Of note, functional studies have shown a deleterious effect of this variant, resulting in the creation of a new splice site (Messiaen 1999 PMID: 11258625, Ars 2000 PMID:10607834, Messiaen 2000 PMID:10862084). In summary, this variant is classified as pathogenic based on the data above (presence of this variant in affected probands, presence as a de novo and predicted impact to protein). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Apr 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000354, PS1_S). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 10607834, 10862084, 10543400, 22155606, 19076627, PS4_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics, University of Zurich	May 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 489 of the NF1 protein (p.Tyr489Cys). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs137854557, gnomAD 0.007%). This missense change has been observed in individuals with neurofibromatosis type 1 (PMID: 10543400, 10607834, 10862084, 11258625, 19076627, 22155606, 22190595). ClinVar contains an entry for this variant (Variation ID: 354). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. Studies have shown that this missense change results in skipping of 62 nucleotides in exon 13 (referred to as exon 10b in the literature) and introduces a premature termination codon (PMID: 10543400, 10607834, 11258625). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 08, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PS4,PP4,PP5. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jan 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Dec 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS3+PS4+PP4+PM6_Supporting+PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	NHS Central & South Genomic Laboratory Hub	Jul 01, 2024	- -

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2023	Peer-reviewed experimental studies have demonstrated that this variant causes aberrant splicing resulting in a nonsense variant (p.Tyr489*) in the NF1 mRNA which causes premature termination of NF1 protein synthesis (PMID: 10543400 (1999), 11258625 (1999), and 10607834 (2000)). It has been reported in numerous Neurofibromatosis type 1 patients in the published literature (PMID: 23758643 (2013), 23668869 (2013), and 26740943 (2015)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 06, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2023	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals and families with NF1. In some published literature, this variant is referred to as 1466del62. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10543400, 11258625, and 10607834) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2023	Exonic splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Osborn and Upadhyaya, 1999; Messiaen et al., 2000; Nemethova et al., 2013); In silico analysis supports a deleterious effect on splicing; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29685074, 26056819, 12807981, 10862084, 10543400, 31533797, 34694046, 29922827, 34427956, 11258625, 10607834, 24803665, 25919870, 11258624, 12095621, 27074763, 19076627, 11735023, 23758643, 22155606, 15863657, 22190595, 15994866, 29666462, 29522274, 12566521, 30014477, 30290804, 30308447, 23668869, 30530636, 31766501, 31717729, 31370276, 29625052, 33372952, 31589614, 31776437, 34308104, 34945792, 33999308, 34992632) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	NF1: PVS1, PM6, PS4:Moderate, PM2:Supporting, PP4 -

Neurofibromatosis, type 1;C4024216:Tibial pseudarthrosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital

Nov 10, 2018

- -

Abnormality of the skin

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

NF1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2024

The NF1 c.1466A>G variant is predicted to result in the amino acid substitution p.Tyr489Cys. This variant has been reported in many individuals with neurofibromatosis type 1 (see for example - Messiaen et al. 1999. PubMed ID: 11258625; Table S2, Laycock-van Spyk et al. 2011. PubMed ID: 22155606; Tsipi et al. 2018. PubMed ID: 30308447). Splicing analysis found this variant results in aberrant splicing that is predicted to result in a frameshift and premature protein termination (Messiaen et al. 1999. PubMed ID: 11258625; Table S1, Zhang et al. 2015. PubMed ID: 26056819). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and has been interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/354/). This variant is interpreted as pathogenic. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

Rhabdomyosarcoma

Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Sep 01, 2020

- -

Neurofibromatosis-Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

May 23, 2023

This sequence variant is a single nucleotide substitution (A>G) at position 1466 of the coding sequence of the NF1 gene that results in a tyrosine to cysteine amino acid change at residue 489 of the neurofibromin 1 protein. Additiolly, experimental evidence confirms that this variant generates an altertive splice site that causes exon skipping and generates an early termition codon at residue 489 (PMID: 11258625). This is a previously reported, recurrent variant (ClinVar 354) that has been observed in many individuals from cohorts of neurofibromatosis patients (PMID: 11258625, 23758643, 34427956). This variant is present in 3 of 250646 alleles (0.0012%) in the gnomAD population dataset. Multiple bioinformatic tools predict that this tyrosine to cysteine amino acid change would be neutral, and the Tyr489 residue at this position is highly conserved across the vertebrate species examined. Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM2, PP3, PS3, PS4 -

Juvenile myelomonocytic leukemia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 25, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2014

The p.Y489C pathogenic mutation (also known as c.1466A>G), located in coding exon 13 of the NF1 gene, results from an A to G substitution at nucleotide position 1466. This is a recurrent mutation that has been detected in multiple cohorts of NF1 patients (<span style="background-color: initial;">Messiaen LM et al. Genet. Med. 1999; 1(6):248-53,<span style="background-color: initial;">Nemethova M et al. Ann. Hum. Genet. 2013 Sep; 77(5):364-79, Ko JM et al. Pediatr. Neurol. 2013 Jun; 48(6):447-53). Messiaen et al (1999) first described this mutation in 5 patients meeting NIH criteria for NF1 and demonstrated that this alteration creates a novel splice site, resulting in skipping of the last 62 nucleotides of coding exon 13 and truncation of the protein. In Nemethova et al (2013), this mutation was observed to segregate with disease in a patient meeting NIH criteria for NF1 and her twin daughters, in whom cafe au lait spots and axial/inguinal freckling were present in infancy. Functional studies performed in this study were also consistent with a splicing defect resulting in a truncated protein. Based on the available evidence, p.Y489C is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

.;D;.;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;L;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.3

.;D;D;D;D

REVEL

Uncertain

0.40

Sift

Benign

0.035

.;D;D;T;D

Sift4G

Benign

0.24

.;T;T;D;T

Polyphen

0.99

D;B;D;.;.

Vest4

0.76, 0.75, 0.73

MVP

0.84

MPC

1.5

ClinPred

0.90

GERP RS

5.3

Varity_R

0.17

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.99

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over