6-31779234-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006295.3(VARS1):c.3459C>T(p.Tyr1153Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,606,126 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 36 hom. )

Consequence

VARS1
NM_006295.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.427

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 6-31779234-G-A is Benign according to our data. Variant chr6-31779234-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 774865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.427 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00366 (557/152336) while in subpopulation NFE AF = 0.00472 (321/68018). AF 95% confidence interval is 0.00429. There are 3 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3 link	c.3459C>T	p.Tyr1153Tyr	synonymous_variant	Exon 29 of 30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6
VARS1	XM_005249362.3 link	c.3462C>T	p.Tyr1154Tyr	synonymous_variant	Exon 29 of 30		XP_005249419.1
VARS1	XM_047419296.1 link	c.3462C>T	p.Tyr1154Tyr	synonymous_variant	Exon 28 of 29		XP_047275252.1
VARS1	XM_047419297.1 link	c.3459C>T	p.Tyr1153Tyr	synonymous_variant	Exon 28 of 29		XP_047275253.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8 link	c.3459C>T	p.Tyr1153Tyr	synonymous_variant	Exon 29 of 30	1	NM_006295.3	ENSP00000364815.3		P26640-1
VARS1	ENST00000463184.1 link	n.615C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

556

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00470

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00442

AC:

1009

AN:

228462

AF XY:

0.00457

show subpopulations

Gnomad AFR exome

AF:

0.0000736

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.0299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00508

Gnomad NFE exome

AF:

0.00482

Gnomad OTH exome

AF:

0.00511

GnomAD4 exome

AF:

0.00371

AC:

5396

AN:

1453790

Hom.:

Cov.:

AF XY:

0.00382

AC XY:

2761

AN XY:

723464

show subpopulations

African (AFR)

AF:

0.000448

AC:

AN:

33470

American (AMR)

AF:

0.00166

AC:

AN:

44498

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

706

AN:

26052

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.00211

AC:

182

AN:

86082

European-Finnish (FIN)

AF:

0.00544

AC:

255

AN:

46850

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00349

AC:

3881

AN:

1111252

Other (OTH)

AF:

0.00437

AC:

263

AN:

60166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

390

781

1171

1562

1952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00366

AC:

557

AN:

152336

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41582

American (AMR)

AF:

0.00242

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00248

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00650

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00472

AC:

321

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

113

141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00787

Hom.:

Bravo

AF:

0.00303

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

VARS1: BP4, BP7, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

2.6

(source)

DANN

Benign

0.75

PhyloP100

-0.43

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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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6-31779234-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over