6-31779234-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006295.3(VARS1):c.3459C>T(p.Tyr1153=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.427

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3459C>T	p.Tyr1153=	synonymous_variant	29/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3462C>T	p.Tyr1154=	synonymous_variant	29/30
VARS1	XM_047419296.1	c.3462C>T	p.Tyr1154=	synonymous_variant	28/29
VARS1	XM_047419297.1	c.3459C>T	p.Tyr1153=	synonymous_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3459C>T	p.Tyr1153=	synonymous_variant	29/30	1	NM_006295.3	P1
VARS1	ENST00000463184.1	n.615C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 556 AN: 152218 Hom.: 3 Cov.: 32

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

GnomAD3 exomes AF: 0.00442 AC: 1009 AN: 228462 Hom.: 12 AF XY: 0.00457 AC XY: 578 AN XY: 126596

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 SAS exome AF: 0.00209

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.: 36 Cov.: 32 AF XY: 0.00382 AC XY: 2761 AN XY: 723464

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00166

Gnomad4 ASJ exome AF: 0.0271

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00211

Gnomad4 FIN exome AF: 0.00544

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74500

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00650

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00787 Hom.: 4

Bravo AF: 0.00303

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	VARS1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	2.6
Dann	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs61730576; hg19: chr6-31747011; COSMIC: COSV100791877; COSMIC: COSV100791877;