chr17-31326241-G-A

Variant names:

• chr17-31326241-G-A
• rs148540952
• NM_001042492.3:c.5257G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BP4_Moderate BP6 BS2_Supporting

The NM_001042492.3(NF1):​c.5257G>A​(p.Val1753Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,608,462 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. V1753L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 9.54
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_001042492.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.26261556).
• BP6: Variant 17-31326241-G-A is Benign according to our data. Variant chr17-31326241-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141594.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=1, Likely_benign=2}.
• BS2: High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.5257G>A	p.Val1753Ile	missense_variant	Exon 37 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.5194G>A	p.Val1732Ile	missense_variant	Exon 36 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.5257G>A	p.Val1753Ile	missense_variant	Exon 37 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000369 AC: 9 AN: 244122 AF XY: 0.0000227

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000893 AC: 13 AN: 1456302 Hom.: 0 Cov.: 32 AF XY: 0.00000690 AC XY: 5 AN XY: 724722

African (AFR) AF: 0.000329 AC: 11 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

African (AFR) AF: 0.000121 AC: 5 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Nov 23, 2015

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1753I variant (also known as c.5257G>A), located in coding exon 37 of the NF1 gene, results from a G to A substitution at nucleotide position 5257. The valine at codon 1753 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs148540952. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than110000alleles tested) in our clinical cohort.This amino acid position is completely conserved on sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.V1753I remains unclear. -

Feb 16, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:1 Benign:1

Mar 12, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.5257G>A; p.Val1753Ile variant (rs148540952), also known as c.5194G>A; p.Val1732Ile for NM_000267, is reported in the ClinVar database (Variation ID: 141594). This variant is found in the African population with an allele frequency of 0.04% (10/24782 alleles) in the Genome Aggregation Database. The valine at codon 1753 is highly conserved, but computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant is uncertain at this time. -

Oct 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29360550) -

Neurofibromatosis, type 1 Benign:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 11, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;T
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.;.
PhyloP100		9.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.13	T;T;T
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.65	P;P;.
Vest4		0.72
MVP		0.54
MPC		1.4
ClinPred		0.23	T
GERP RS		5.6
Varity_R		0.21
gMVP		0.44
Mutation Taster		=21/79	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs148540952; hg19: chr17-29653259; COSMIC: COSV55985821;