Variant rs201047812 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_001042492.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-31232821-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 579791.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant where missense usually causes diseases, NF1

BP4

Computational evidence support a benign effect (MetaRNN=0.10001889).

BP6

Variant 17-31232821-G-A is Benign according to our data. Variant chr17-31232821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141451.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=14, Likely_benign=5}.

BS2

High AC in GnomAd4 at 20 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	UniProt
NF1	NM_001042492.3 linkuse as main transcript	c.3436G>A	p.Val1146Ile	missense_variant	26/58	ENST00000358273.9
NF1	NM_000267.3 linkuse as main transcript	c.3436G>A	p.Val1146Ile	missense_variant	26/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9 linkuse as main transcript	c.3436G>A	p.Val1146Ile	missense_variant	26/58	1	NM_001042492.3	P1	P21359-1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

20

AN:

152068

Hom.:

0

Cov.:

31

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

32

AN:

251366

Hom.:

0

AF XY:

0.000103

AC XY:

14

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

303

AN:

1461862

Hom.:

0

Cov.:

32

AF XY:

0.000184

AC XY:

134

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000256

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000132

AC:

20

AN:

152068

Hom.:

0

Cov.:

31

AF XY:

0.000148

AC XY:

11

AN XY:

74264

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000590

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000271

Hom.:

0

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.000107

AC:

13

EpiCase

AF:

0.00

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neurofibromatosis, type 1

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Oct 26, 2020	- -

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2016	The p.Val1164Ile variant in NF1 has been reported in 3 individuals with Neurofib romatosis type 1 (NF1; Trovo 2004, Mendelian Genes). This variant has also been identified in 11/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201047812). An additional amino a cid change at this position (p.Val1164 Phe) has been reported to occur de novo i n two individuals with NF1 (Mendelian Genes), suggesting that a change at this p osition may not be tolerated. However, valine (Val) at position 1146 is not cons erved in evolutionary distant species, with multiple fish species carrying an is oleucine (Ile) at this position, and raising the possibility that a change at th is position may be tolerated. Additional computational prediction tools suggest that the p.Val1146Ile variant may not impact the protein, though this informatio n is not predictive enough to rule out pathogenicity. In summary, due to conflic ting data, the clinical significance of the p.Val1146Ile variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2019	Variant summary: NF1 c.3436G>A (p.Val1146Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251366 control chromosomes, predominantly observed within the Latino subpopulation (at a frequency of 0.00023) and the in the European (Non-Finnish) subpopulation (at frequency of 0.00019) in the gnomAD database. The variant frequency in the Latino subpopulation is higher than expected for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 (0.00023 vs 0.00021), suggesting that the variant is might be benign. In addition, the variant occurs in certain European subpopulations with even higher frequencies (e.g. in the Bulgarians (0.0015), and in Southern Europeans (0.00026)) further supporting a benign role. The c.3436G>A variant has been reported in the literature in an individual affected with Neurofibromatosis Type 1, however these publications cited the variant as a polymorphism (Trovo_2004, Trovo-Marqui_2005). Therefore these reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1. A co-occurrence with another pathogenic NF1 variant has been reported (NF1 c.3892C>T (p.Gln1298X) in an internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four classified the variant as VUS, while one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2021	The NF1 c.3436G>A; p.Val1146Ile variant (rs201047812) is reported in the literature in individuals affected with neurofibromatosis type 1 or another unspecified cancer, but without clear association with disease (Trovo-Marqui 2005, Tsaousis 2019). This variant is also reported in ClinVar (Variation ID: 141451), and is found in the general population with an overall allele frequency of 0.012% (33/282760 alleles) in the Genome Aggregation Database. The valine at codon 1146 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.251). Due to limited information, the clinical significance of the p.Val1146Ile variant is uncertain at this time. References: Trovo-Marqui AB et al. High frequencies of plexiform neurofibromas, mental retardation, learning difficulties, and scoliosis in Brazilian patients with neurofibromatosis type 1. Braz J Med Biol Res. 2005 Sep;38(9):1441-7. PMID: 16138229. Tsaousis et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. PMID: 31159747 -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 03, 2023	The frequency of this variant in the general population, 0.00023 (8/35432 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in patients with Neurofibromatosis, type 1 (PMIDs: 23656349 (2014) and 16138229 (2005)) and breast cancer (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). The variant has been reported as a somatic finding in a glioma tumor sample (PMID: 31891871 (2020)). In addition, this variant has been reported in healthy control individuals (PMID: 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	This variant is associated with the following publications: (PMID: 31159747, 15627836, 16138229, 23656349, 31891871) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 23, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2015	Does not segregate with disease in family study (genes with incomplete penetrance);in silico models in agreement (benign);Other data supporting benign classification -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Neurofibromatosis, familial spinal

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Neurofibromatosis-Noonan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Café-au-lait macules with pulmonary stenosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2018

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

0.10

BayesDel_addAF

Benign

-0.34

T

BayesDel_noAF

Benign

-0.44

CADD

Benign

22

DANN

Benign

0.89

DEOGEN2

Benign

0.41

T;.;T

Eigen

Benign

-0.26

Eigen_PC

Benign

0.013

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.18

D

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-0.80

T

MutationAssessor

Benign

-1.3

N;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.76

T

PROVEAN

Benign

0.030

N;N;N

REVEL

Benign

0.25

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;P;.

Vest4

0.25

MVP

0.47

MPC

0.56

ClinPred

0.090

T

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.060

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

rs201047812

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