dbSNP rs376864621: VARS1:p.Gly822Ser (chr6-31781561-C-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_006295.3(VARS1):c.2464G>A(p.Gly822Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

VARS1
NM_006295.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 5.69

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the VARS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.6849 (below the threshold of 3.09). Trascript score misZ: 3.4812 (above the threshold of 3.09). GenCC associations: The gene is linked to combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 6-31781561-C-T is Pathogenic according to our data. Variant chr6-31781561-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 561995.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3 link	c.2464G>A	p.Gly822Ser	missense_variant	Exon 21 of 30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6
VARS1	XM_005249362.3 link	c.2467G>A	p.Gly823Ser	missense_variant	Exon 21 of 30		XP_005249419.1
VARS1	XM_047419296.1 link	c.2467G>A	p.Gly823Ser	missense_variant	Exon 20 of 29		XP_047275252.1
VARS1	XM_047419297.1 link	c.2464G>A	p.Gly822Ser	missense_variant	Exon 20 of 29		XP_047275253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8 link	c.2464G>A	p.Gly822Ser	missense_variant	Exon 21 of 30	1	NM_006295.3	ENSP00000364815.3		P26640-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000162

AC:

AN:

246492

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000988

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000904

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000548

AC:

AN:

1460752

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

Pathogenic:2

Aug 20, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 03, 2018

Neurogenetics group, VIB, Antwerp, Belgium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.42

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.30

MutationAssessor

Pathogenic

3.5

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.96

MutPred

0.94

Gain of glycosylation at G822 (P = 0.0384);

MVP

0.94

MPC

1.3

ClinPred

0.98

GERP RS

4.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Varity_R

0.70

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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