6-31779470-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_006295.3(VARS1):c.3355C>T(p.Arg1119Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.91

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VARS1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 6-31779470-G-A is Pathogenic according to our data. Variant chr6-31779470-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3355C>T	p.Arg1119Cys	missense_variant	28/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3358C>T	p.Arg1120Cys	missense_variant	28/30
VARS1	XM_047419296.1	c.3358C>T	p.Arg1120Cys	missense_variant	27/29
VARS1	XM_047419297.1	c.3355C>T	p.Arg1119Cys	missense_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3355C>T	p.Arg1119Cys	missense_variant	28/30	1	NM_006295.3	P1
VARS1	ENST00000463184.1	n.511C>T		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000204 AC: 5 AN: 244528 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 133784

Gnomad AFR exome AF: 0.0000668

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460350 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726544

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 20, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Gleeson Lab, University of California San Diego - Department of Neuroscience	Jan 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 28, 2020	The homozygous p.Arg1119Cys variant in VARS1 was identified by our study in collaboration with the Gleeson Lab in an individual with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (PMID: 30755602). Please note that this variant may also be submitted to ClinVar by the Gleeson Lab. This variant was reported in 3 total Egyptian individuals with neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy, segregated with disease in 2 affected relatives from 1 family (PMID: 30755602), and has been identified in 0.007% (1/14966) of African chromosomes, 0.005% (1/18238) of East Asian chromosomes, and 0.005% (1/21226) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs149378938). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 559839). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in affected homozygotes increases the likelihood that the p.Arg1119Cys variant is pathogenic (PMID: 30755602). Multiple variants with the same function as p.Arg1119Cys variant have been reported in association with disease in the literature and the variant is located in a region of VARS1 that is essential to protein function, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 30755602). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM1, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	4.7	H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.69
MPC		1.6
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.47
gMVP		0.92

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: rs149378938; hg19: chr6-31747247;