6-31779171-C-G

Position:

chr6-31779171-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_006295.3(VARS1):c.3522G>C(p.Gln1174His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,605,450 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 4 hom. )

Consequence

VARS1
NM_006295.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.394

Variant links:

Genes affected

VARS1 (HGNC:12651): (valyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. The protein encoded by this gene belongs to class-I aminoacyl-tRNA synthetase family and is located in the class III region of the major histocompatibility complex. [provided by RefSeq, Jul 2008]

VARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), VARS1. . Gene score misZ 2.6849 (greater than the threshold 3.09). Trascript score misZ 3.4812 (greater than threshold 3.09). GenCC has associacion of gene with combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.007817298).

BP6

Variant 6-31779171-C-G is Benign according to our data. Variant chr6-31779171-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3040947.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0015 (228/152346) while in subpopulation AFR AF= 0.00522 (217/41582). AF 95% confidence interval is 0.00465. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS1	NM_006295.3 linkuse as main transcript	c.3522G>C	p.Gln1174His	missense_variant	29/30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6
VARS1	XM_005249362.3 linkuse as main transcript	c.3525G>C	p.Gln1175His	missense_variant	29/30		XP_005249419.1
VARS1	XM_047419296.1 linkuse as main transcript	c.3525G>C	p.Gln1175His	missense_variant	28/29		XP_047275252.1
VARS1	XM_047419297.1 linkuse as main transcript	c.3522G>C	p.Gln1174His	missense_variant	28/29		XP_047275253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8 linkuse as main transcript	c.3522G>C	p.Gln1174His	missense_variant	29/30	1	NM_006295.3	ENSP00000364815.3		P26640-1

Frequencies

GnomAD3 genomes

AF:

0.00150

AC:

228

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00523

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000423

AC:

AN:

224664

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

124204

show subpopulations

Gnomad AFR exome

AF:

0.00630

Gnomad AMR exome

AF:

0.000249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000203

Gnomad OTH exome

AF:

0.000182

GnomAD4 exome

AF:

0.000182

AC:

265

AN:

1453104

Hom.:

Cov.:

AF XY:

0.000151

AC XY:

109

AN XY:

722774

show subpopulations

Gnomad4 AFR exome

AF:

0.00630

Gnomad4 AMR exome

AF:

0.000418

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000500

GnomAD4 genome

AF:

0.00150

AC:

228

AN:

152346

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.00522

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.00171

ExAC

AF:

0.000462

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2022

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. -

VARS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.9

DANN

Benign

0.97

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.76

M_CAP

Benign

0.021

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.8

REVEL

Benign

0.074

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.88

Vest4

0.21

MutPred

0.37

Loss of glycosylation at P1171 (P = 0.1614);

MVP

0.22

MPC

0.64

ClinPred

0.012

GERP RS

0.45

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.018

gMVP

0.41

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