chr6-31779171-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/22 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, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.394

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: Benign. The variant received -20 ACMG points.

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 VariationId is 3040947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006295.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS1	NM_006295.3	MANE Select	c.3522G>C	p.Gln1174His	missense	Exon 29 of 30	NP_006286.1	P26640-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VARS1	ENST00000375663.8	TSL:1 MANE Select	c.3522G>C	p.Gln1174His	missense	Exon 29 of 30	ENSP00000364815.3	P26640-1
VARS1	ENST00000851851.1		c.3567G>C	p.Gln1189His	missense	Exon 29 of 30	ENSP00000521910.1
VARS1	ENST00000851849.1		c.3561G>C	p.Gln1187His	missense	Exon 29 of 30	ENSP00000521908.1

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

GnomAD2 exomes

AF:

0.000423

AC:

AN:

224664

AF XY:

0.000258

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 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

African (AFR)

AF:

0.00630

AC:

209

AN:

33172

American (AMR)

AF:

0.000418

AC:

AN:

43012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25794

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.0000351

AC:

AN:

85576

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51154

Middle Eastern (MID)

AF:

0.000523

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109130

Other (OTH)

AF:

0.000500

AC:

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00150

AC:

228

AN:

152346

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00522

AC:

217

AN:

41582

American (AMR)

AF:

0.000588

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000515

Hom.:

Bravo

AF:

0.00171

ExAC

AF:

0.000462

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

VARS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.9

(source)

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

PhyloP100

-0.39

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

Mutation Taster

=86/14

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over