rs769369302

chr6-31779723-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_006295.3(VARS1):c.3173G>A(p.Arg1058Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 3.60

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VARS1
• PP5: Variant 6-31779723-C-T is Pathogenic according to our data. Variant chr6-31779723-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-31779723-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3173G>A	p.Arg1058Gln	missense_variant	27/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3176G>A	p.Arg1059Gln	missense_variant	27/30
VARS1	XM_047419296.1	c.3176G>A	p.Arg1059Gln	missense_variant	26/29
VARS1	XM_047419297.1	c.3173G>A	p.Arg1058Gln	missense_variant	26/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3173G>A	p.Arg1058Gln	missense_variant	27/30	1	NM_006295.3	P1
VARS1	ENST00000463184.1	n.329G>A		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246138 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460744 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 726688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74284

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000840 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Aug 17, 2021	ACMG classification criteria: PS3 supporting, PS4 supporting, PM2 moderate, PM3 moderate -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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There is one more families with similar phenotype -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.10
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.11	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.74		Loss of methylation at R1058 (P = 0.0222);
MVP		0.53
MPC		1.4
ClinPred		0.95	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.34
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs769369302; hg19: chr6-31747500; COSMIC: COSV100791806; COSMIC: COSV100791806;