17-31232869-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 3P and 7B. PM1 PP2 BP4_Moderate BP6 BS2

The NM_001042492.3(NF1):c.3484A>G(p.Met1162Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. M1162L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• 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 Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001042492.3
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.100688875).
• BP6: Variant 17-31232869-A-G is Benign according to our data. Variant chr17-31232869-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219750.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.3484A>G	p.Met1162Val	missense_variant	26/58	ENST00000358273.9
NF1	NM_000267.3	c.3484A>G	p.Met1162Val	missense_variant	26/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.3484A>G	p.Met1162Val	missense_variant	26/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251296 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461852 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

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: 0.0000394 AC: 6 AN: 152184 Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5 AN XY: 74344

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00115

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	May 30, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 25, 2015	The p.M1162V variant (also known as c.3484A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3484. The methionine at codon 1162 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.M1162Vremains unclear. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The NF1 p.M1162V variant was identified in one of 200 proband chromosomes (frequency: 0.005) from individuals or families with a clinical diagnosis of Neurofibromatosis type 1 (NF1) (Wu-Chou_2018_PMID:30290804). The variant was also identified in one of 34 proband chromosomes (frequency: 0.029) from individuals with a clinical diagnosis of Noonan syndrome (Koh_2019_PMID:30784236). This patient inherited the p.M1162V variant from his father and both did not meet clinical criteria for NF1 (Koh_2019_PMID:30784236). The variant was also identified in dbSNP (ID: rs773968270) and in ClinVar (conflicting interpretations of pathogenicity; classified as uncertain significance by Ambry Genetics and likely benign by Invitae for Neurofibromatosis type 1 and Hereditary cancer-predisposing syndrome). The variant was not identified in COSMIC or LOVD 3.0. The variant was identified in control databases in 32 of 282690 chromosomes at a frequency of 0.000113 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: East Asian in 31 of 19924 chromosomes (freq: 0.001556) and European (non-Finnish) in 1 of 129068 chromosomes (freq: 0.000008), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Met1162 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 13, 2022

- -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Neurofibromatosis, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 30, 2021

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Uncertain	0.63	D;.;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.92
MutPred		0.34		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;
MVP		0.86
MPC		1.1
ClinPred		0.14	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.64

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: rs773968270; hg19: chr17-29559887;