6-31785268-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_006295.3(VARS1):c.1325G>A(p.Arg442Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,762 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

VARS1
NM_006295.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.43

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
combined oxidative phosphorylation defect type 20
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006295.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3 link	c.1325G>A	p.Arg442Gln	missense_variant	Exon 10 of 30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VARS1	ENST00000375663.8 link	c.1325G>A	p.Arg442Gln	missense_variant	Exon 10 of 30	1	NM_006295.3	ENSP00000364815.3	P26640-1
VARS1	ENST00000489979.1 link	n.636G>A		non_coding_transcript_exon_variant	Exon 5 of 5	3
VARS1	ENST00000495010.5 link	n.868G>A		non_coding_transcript_exon_variant	Exon 7 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460762

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726698

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000629

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

Pathogenic:1

Sep 03, 2018

Neurogenetics group, VIB, Antwerp, Belgium

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Uncertain:1

May 22, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.5

PhyloP100

5.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.52

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.73

MutPred

0.88

Loss of MoRF binding (P = 0.0659);

MVP

0.71

MPC

1.4

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.9

Varity_R

0.78

gMVP

0.88

Mutation Taster

=6/94

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over