6-31779102-A-C

Variant names:

• chr6-31779102-A-C
• NM_006295.3:c.3591T>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_006295.3(VARS1):​c.3591T>G​(p.Pro1197Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,458,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: VARS1 NM_006295.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -8.18
• Publications: 0 publications found

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

Y_RNA (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 6-31779102-A-C is Benign according to our data. Variant chr6-31779102-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2656418.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-8.18 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3	c.3591T>G	p.Pro1197Pro	synonymous_variant	Exon 29 of 30	ENST00000375663.8	NP_006286.1
VARS1	XM_005249362.3	c.3594T>G	p.Pro1198Pro	synonymous_variant	Exon 29 of 30		XP_005249419.1
VARS1	XM_047419296.1	c.3594T>G	p.Pro1198Pro	synonymous_variant	Exon 28 of 29		XP_047275252.1
VARS1	XM_047419297.1	c.3591T>G	p.Pro1197Pro	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	c.3591T>G	p.Pro1197Pro	synonymous_variant	Exon 29 of 30	1	NM_006295.3	ENSP00000364815.3
Y_RNA	ENST00000364685.1	n.-197T>G		upstream_gene_variant		6
VARS1	ENST00000463184.1	n.*128T>G		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1458040 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4 AN XY: 725182

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110622

Other (OTH) AF: 0.00 AC: 0 AN: 60226

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

VARS1: PM2:Supporting, BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0050
DANN	Benign	0.49
PhyloP100		-8.2
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

Other links and lift over

hg19: chr6-31746879;