rs145191978

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP6BS2_Supporting

The NM_001042492.3(NF1):c.1588G>A(p.Val530Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00018 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

NF1
NM_001042492.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6O:1

Conservation

PhyloP100: 6.28

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 Likely_benign. Variant got -1 ACMG points.

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.

BP6

Variant 17-31219065-G-A is Benign according to our data. Variant chr17-31219065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141369.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, not_provided=1}.

BS2

High AC in GnomAd4 at 7 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/exons	MANE	Protein	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.1588G>A	p.Val530Ile	missense_variant	14/58	ENST00000358273.9	NP_001035957.1	P21359-1
NF1	NM_000267.3 linkuse as main transcript	c.1588G>A	p.Val530Ile	missense_variant	14/57		NP_000258.1	P21359-2
NF1	NM_001128147.3 linkuse as main transcript	c.1588G>A	p.Val530Ile	missense_variant	14/15		NP_001121619.1	P21359-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.1588G>A	p.Val530Ile	missense_variant	14/58	1	NM_001042492.3	ENSP00000351015.4		P21359-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000797

AC:

AN:

251002

Hom.:

AF XY:

0.0000959

AC XY:

AN XY:

135620

show subpopulations

Gnomad AFR exome

AF:

0.0000618

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:

0.000158

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000194

AC:

284

AN:

1461588

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

141

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000461

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74218

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000131

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:1Benign:1Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	This participant was tested at multiple clinical laboratories with differing classifications. The variant was classified, most recently, as Uncertain on 04-29-2017 by GTR ID 26957.AT51 Variant was also classified as Uncertain significance and reported in October 2015 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Nov 11, 2021	The NF1 c.1588G>A (p.Val530Ile) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-29546083-G-A?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PP2; PMID: 27535533). This variant has been observed in an individual with pheochromocytoma who also harbored a pathogenic variant in SDHB (BP5; PMID: 23407919). To our knowledge, this variant has not been reported in individuals with Neurofibromatosis type 1. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP2, BP5. -

not provided

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NF1 p.V530I variant was identified in an individual with pheochromocytoma who was hypertensive but did not exhibit any Neurofibromatosis type 1 symptoms; the patient also had another variant in the SDHB gene which authors reported to be pathogenic (Sjursen_2013_PMID_23407919). The variant was identified in dbSNP (ID: rs145191978) and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae and St. Jude Children's Research Hospital Clinical Genomics Lab, andas likely benign by GeneDx). The variant was identified in control databases in 21 of 282376 chromosomes at a frequency of 0.00007437 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 19 of 128982 chromosomes (freq: 0.000147), Other in 1 of 7214 chromosomes (freq: 0.000139) and African in 1 of 24882 chromosomes (freq: 0.00004), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The p.V530 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 01, 2020	This variant is associated with the following publications: (PMID: 23407919) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 23, 2015	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence -

NF1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2024

The NF1 c.1588G>A variant is predicted to result in the amino acid substitution p.Val530Ile. This variant was identified in an individual with adrenal pheochromocytoma and hypertension, but who had no signs or symptoms of neurofibromatosis. The individual also carried a pathogenic variant in the SDHB gene (Sjursen et al. 2013. PubMed ID: 23407919). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/141369/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 08, 2023

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been identified in at least one clinically healthy individual. This variant has been seen where an alternate explanation for disease was also identified. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 27, 2024

- -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2019

This alteration is classified as likely 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

Benign

0.19

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

.;D;.;.;T

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

D;D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.47

T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Uncertain

2.3

M;M;M;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.79

.;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Uncertain

0.020

.;D;D;D;T

Sift4G

Uncertain

0.0070

.;D;D;D;D

Polyphen

1.0

D;D;B;.;.

Vest4

0.67, 0.52, 0.24

MVP

0.70

MPC

1.5

ClinPred

0.22

GERP RS

3.7

Varity_R

0.15

gMVP

0.49

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