17-31232830-A-G

Position:

chr17-31232830-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The ENST00000358273.9(NF1):c.3445A>G(p.Met1149Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,868 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NF1
ENST00000358273.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:1

Conservation

PhyloP100: 8.88

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 10 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in ENST00000358273.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31232832-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.891

PP5

Variant 17-31232830-A-G is Pathogenic according to our data. Variant chr17-31232830-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 527517.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Pathogenic=7, Uncertain_significance=1}. Variant chr17-31232830-A-G is described in Lovd as [Pathogenic]. Variant chr17-31232830-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.3445A>G	p.Met1149Val	missense_variant	26/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3 linkuse as main transcript	c.3445A>G	p.Met1149Val	missense_variant	26/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.3445A>G	p.Met1149Val	missense_variant	26/58	1	NM_001042492.3	ENSP00000351015	P1	P21359-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251376

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135858

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

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:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 05, 2022	The NF1 c.3445A>G (p.Met1149Val) variant results in the substitution of a methionine at amino acid position 1149 with valine. This variant has been reported in at least 38 heterozygous individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population (version 2.1.1). The Met1149 residue has been identified as a non-truncating hotspot in the gene (Koczkowska et al. 2020) with additional pathogenic variants that have been identified in patients with neurofibromatosis type 1 within two residues on each side of the variant. Three other amino acid changes due to missense variants at the Met1149 residue that have been reported in the literature and found in at least 13 individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.3445A>G (p.Met1149Val) variant is classified as pathogenic for neurofibromatosis type 1. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 19, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1149 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16944272, 27322474; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 527517). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23656349, 24711935, 28706617, 31595648; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1149 of the NF1 protein (p.Met1149Val). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NF1: PM2, PM5, PS4:Moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: impaired ability to inhibit GTP-Ras activity (Long et al., 2022); This variant is associated with the following publications: (PMID: 23656349, 26681766, 28706617, 24711935, 29617658, 29095814, 31618753, 31370276, 25486365, 2121369, 22807134, 27322474, 29290338, 16944272, 31776437, 31595648, 33884301, 34694046) -

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

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4+PP3+PP4+PM5+PP1_Moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	NF1 NM_000267.3 exon 26 p.Met1149Val (c.3445A>G): This variant has been reported in the literature in multiple individuals with features of neurofibromatosis type I, segregating with disease in several affected family members (van Minkelen 2014 PMID:23656349, Domingues 2014 PMID:24711935, Koczkowska 2020 PMID:31595648). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:527517). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, this variant is classified as pathogenic based on the data above. -

NF1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2023

The NF1 c.3445A>G variant is predicted to result in the amino acid substitution p.Met1149Val. This missense variant has been documented in several individuals with neurofibromatosis type 1 (Domingues et al. 2014. PubMed ID: 24711935; Gengel et al. 2017. PubMed ID: 28706617; Koczkowska et al. 2020. PubMed ID: 31595648). In addition, alternative missense changes at the same codon (p.Met1149Thr, p.Met1149Ile) have been documented to be pathogenic individuals with neurofibromatosis type 1 (Koczkowska et al. 2020. PubMed ID: 31595648; Evans et al. 2016. PubMed ID: 27322474; Griffiths et al. 2007. PubMed ID: 16944272) and are interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/527517/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29559848-A-G). This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2017

The p.M1149V variant (also known as c.3445A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3445. The methionine at codon 1149 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was detected in an individual who met diagnostic criteria for Neurofibromatosis type 1 (NF1) and also carried a diagnosis of respiratory chain complex I deficiency (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27). In another study, this alteration was detected in one individual from a cohort of NF1 patients, but it is unclear whether this individual met diagnostic criteria for NF1 (Domingues S et al. Case Rep Genet, 2014 Mar;2014:423071). A different alteration located at the same position, p.M1149I, was detected as a de novo occurrence in one individual; however, it is unclear whether this individual met diagnostic criteria for NF1 (Griffiths S et al. Fam. Cancer, 2007;6:21-34). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Neurofibromatosis-Noonan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The observed missense variant c.3445A>G(p.Met1149Val) in NF1 gene has been reported previously in heterozygous state in multiple individuals with neurofibromatosis (Koczkowska M, et al., 2020, Domingues S, et al., 2014 ). The Met1149 residue has been identified as a non-truncating hotspot in the gene with additional pathogenic variants that have been identified in patients with neurofibromatosis type 1 within two residues on each side of the variant (Koczkowska et al. 2020). Three other amino acid changes due to missense variants at the Met1149 residue that have been reported. The (p.Met1149Val) variant is reported with 0.0004% allele frequecny in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. Multiple lines of computational evidence (Polyphen- probably damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid Met at position 1149 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Met1149Val in NF1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;.;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0030

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.96

D;B;.

Vest4

0.98

MutPred

0.66

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;

MVP

0.87

MPC

1.1

ClinPred

0.90

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.56

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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