rs1187097568

Positions:

• chr17-31232830-A-G
• chr17-31232830-A-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(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 Likely pathogenic (★★). 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 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 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 NM_001042492.3
• 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 where missense usually causes diseases, NF1
• 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 [Likely_pathogenic]. Clinvar id is 527517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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	UniProt
NF1	NM_001042492.3	c.3445A>G	p.Met1149Val	missense_variant	26/58	ENST00000358273.9
NF1	NM_000267.3	c.3445A>G	p.Met1149Val	missense_variant	26/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3445A>G	p.Met1149Val	missense_variant	26/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251376 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

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: 2 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

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.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

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	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	- -

not provided Pathogenic:2

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) -

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. -

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

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
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	D
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

Other links and lift over

dbSNP: rs1187097568; hg19: chr17-29559848; COSMIC: COSV100646550; COSMIC: COSV100646550;