6-31779043-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006295.3(VARS1):c.3650G>A(p.Arg1217His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000143 in 1,612,670 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1217C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:4
• Conservation: PhyloP100: 2.05

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, VARS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.014083326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VARS1	NM_006295.3	c.3650G>A	p.Arg1217His	missense_variant	29/30	ENST00000375663.8
VARS1	XM_005249362.3	c.3653G>A	p.Arg1218His	missense_variant	29/30
VARS1	XM_047419296.1	c.3653G>A	p.Arg1218His	missense_variant	28/29
VARS1	XM_047419297.1	c.3650G>A	p.Arg1217His	missense_variant	28/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VARS1	ENST00000375663.8	c.3650G>A	p.Arg1217His	missense_variant	29/30	1	NM_006295.3	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 60 AN: 242850 Hom.: 0 AF XY: 0.000188 AC XY: 25 AN XY: 133090

Gnomad AFR exome AF: 0.00240

Gnomad AMR exome AF: 0.000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 155 AN: 1460322 Hom.: 0 Cov.: 32 AF XY: 0.0000991 AC XY: 72 AN XY: 726488

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000450

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74496

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000477 Hom.: 0

Bravo AF: 0.000680

ESP6500AA AF: 0.00133 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000264 AC: 31

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 04, 2021	- -
Likely pathogenic, flagged submission	clinical testing	Baylor Genetics	Feb 13, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 01, 2021	The VARS1 c.3650G>A (p.Arg1217His) variant is a missense variant that has been reported in one study in which it was identified in a homozygous state in eight similarly affected individuals from a large consanguineous family and shown to segregate with disease (Alsemari et al. 2017). The proband from the family presented with tonic-clonic seizures from four months of age, with severe developmental delay, including a severe speech impairment, noted from one year of age. Severe growth hormone failure and skeletal abnormalities, including severe osteomalacia and multiple looser zones and fractures, microcephaly, scoliosis, and kyphosis were also noted. Brain MRI showed cerebellar atrophy however cortical abnormalities were not observed. The p.Arg1217His variant is reported at a frequency of 0.002360 in the African /African American population of the Genome Aggregation Database, a frequency that is higher than would be expected for a rare autosomal recessive disease. Homology modelling shows that residue Arg1217 is located within the C-terminal coiled-coil domain of VARS1 and is thought to play a role in the specific recognition of tRNA. The p.Arg1217His variant is predicted to abolish this function (Alsemari et al. 2017). Based on the available evidence and application of the ACMG criteria, the p.Arg1217His variant is classified as a variant of uncertain significance for neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29137650) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	0.18
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.70	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.23
MPC		1.2
ClinPred		0.066	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.10
gMVP		0.35

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: rs368075745; hg19: chr6-31746820;