17-31338739-C-G

Position:

chr17-31338739-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001042492.3(NF1):c.6855C>G(p.Tyr2285*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NF1
NM_001042492.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.69

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:

NF1 (HGNC:):

NF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-31338739-C-G is Pathogenic according to our data. Variant chr17-31338739-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 439973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31338739-C-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.6855C>G	p.Tyr2285*	stop_gained	46/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 linkuse as main transcript	c.6792C>G	p.Tyr2264*	stop_gained	45/57		NP_000258.1	P21359-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.6855C>G	p.Tyr2285*	stop_gained	46/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

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:

0.00000398

AC:

AN:

251198

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461050

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726870

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

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:

0.0000540

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:3

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-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 02, 2023	This sequence change creates a premature translational stop signal (p.Tyr2264*) in the NF1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs772295894, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neurofibromatosis type 1 (PMID: 9385374, 17311297, 23668869, 23913538, 24232412). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 439973). Studies have shown that this premature translational stop signal results in skipping of exon 45, but is expected to preserve the integrity of the reading-frame (PMID: 9385374, 16870183, 22925204). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2024	Published functional studies demonstrate a damaging effect: most show aberrant splicing resulting in skipping of the in-frame exon 45, with one study additionally showing transcripts demonstrating skipping of exons 45 and 46 as well as transcripts with normal splicing; of note, normally spliced transcripts include the nonsense (Y2264*) change, presumed to lead to premature termination (PMID: 16870183, 9385374, 10862084, 17311297); In silico analysis is inconclusive as to whether the variant alters gene splicing; This variant is associated with the following publications: (PMID: 29625052, 24789688, 17311297, 18503770, 9385374, 24676943, 28891274, 31370276, 22664653, 23668869, 22925204, 30530636, 29100083, 16479075, 26659639, 24232412, 25525159, 16870183, 19142971, 10862084, 16944272, 37073110, 36451132, 23913538, 29122587, 35122187, Park[CaseReport]2014) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NF1: PVS1, PM2, PS2:Moderate, PS4:Moderate, PS3:Supporting -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

The c.6792C>G pathogenic mutation (also known as p.Y2264*), located in coding exon 45 of the NF1 gene, results from a C to G substitution at nucleotide position 6792. This changes the amino acid from a tyrosine to a stop codon within coding exon 45. This mutation has been reported in multiple patients with clinical features of neurofibromatosis type 1 (Messiaen L et al. Hum Genet, 1997 Nov;101:75-80; Wimmer K et al. Hum Mutat, 2007 Jun;28:599-612; Ko JM et al. Pediatr Neurol, 2013 Jun;48:447-53; Stewart DR et al. Genet Med, 2014 Jun;16:448-59; Whitworth J et al. JAMA Oncol, 2016 Mar;2:373-9). In addition, this mutation was detected as de novo in individuals with neurofibromatosis type 1 or epileptic encephalopathy (Sabbagh A et al. Hum Mutat, 2013 Nov;34:1510-8; Hamdan FF et al. Am J Hum Genet, 2017 Nov;101:664-685; Wang X et al. Genes Chromosomes Cancer, 2018 01;57:19-27). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, multiple RNA studies have demonstrated that this mutation primarily disrupts exonic splicing enhancer, leading to skipping of exon 45 (Messiaen L et al. Hum Genet, 1997 Nov;101:75-80; Baralle M et al. FEBS Lett, 2006 Aug;580:4449-56; Hernández-Imaz E et al. Clin Genet, 2013 May;83:462-6; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.97

Vest4

0.99

GERP RS

4.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: -35

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