6-31779044-G-A

Position:

chr6-31779044-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_006295.3(VARS1):c.3649C>T(p.Arg1217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,612,510 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00086 ( 17 hom. )

Consequence

VARS1
NM_006295.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.24

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 -12 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=0.008346707).

BP6

Variant 6-31779044-G-A is Benign according to our data. Variant chr6-31779044-G-A is described in ClinVar as [Benign]. Clinvar id is 3045730.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000729 (111/152340) while in subpopulation EAS AF= 0.0202 (105/5188). AF 95% confidence interval is 0.0171. There are 1 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VARS1	NM_006295.3 linkuse as main transcript	c.3649C>T	p.Arg1217Cys	missense_variant	29/30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6
VARS1	XM_005249362.3 linkuse as main transcript	c.3652C>T	p.Arg1218Cys	missense_variant	29/30		XP_005249419.1
VARS1	XM_047419296.1 linkuse as main transcript	c.3652C>T	p.Arg1218Cys	missense_variant	28/29		XP_047275252.1
VARS1	XM_047419297.1 linkuse as main transcript	c.3649C>T	p.Arg1217Cys	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.3649C>T	p.Arg1217Cys	missense_variant	29/30	1	NM_006295.3	ENSP00000364815.3		P26640-1

Frequencies

GnomAD3 genomes

AF:

0.000736

AC:

112

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0204

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00224

AC:

542

AN:

242426

Hom.:

AF XY:

0.00213

AC XY:

283

AN XY:

132950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0287

Gnomad SAS exome

AF:

0.000626

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000185

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000855

AC:

1249

AN:

1460170

Hom.:

Cov.:

AF XY:

0.000859

AC XY:

624

AN XY:

726416

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0281

Gnomad4 SAS exome

AF:

0.000904

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.000614

GnomAD4 genome

AF:

0.000729

AC:

111

AN:

152340

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0202

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000994

Hom.:

Bravo

AF:

0.000963

ExAC

AF:

0.00214

AC:

251

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

VARS1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 13, 2019

This variant is classified as 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

0.32

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

MetaRNN

Benign

0.0083

MetaSVM

Benign

-0.91

MutationAssessor

Benign

2.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.13

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.50

MVP

0.33

MPC

1.3

ClinPred

0.073

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.24

gMVP

0.52

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