rs1401228799

Variant names:

• chr6-31782540-G-T
• rs1401228799
• NM_006295.3:c.1981C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_006295.3(VARS1):​c.1981C>A​(p.Pro661Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,672 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.25

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the VARS1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 2.6849 (below the threshold of 3.09). Trascript score misZ: 3.4812 (above the threshold of 3.09). GenCC associations: The gene is linked to combined oxidative phosphorylation defect type 20, neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 6-31782540-G-T is Pathogenic according to our data. Variant chr6-31782540-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 522588.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3	c.1981C>A	p.Pro661Thr	missense_variant	Exon 16 of 30	ENST00000375663.8	NP_006286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VARS1	ENST00000375663.8	c.1981C>A	p.Pro661Thr	missense_variant	Exon 16 of 30	1	NM_006295.3	ENSP00000364815.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245476 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460672 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726638

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000574

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Oct 24, 2017

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The patient is homozygous for a missense variant in VARS (c.1981C>A, p.Pro661Thr). Variants in VARS have been linked to a recessive disorder involving cortical atrophy, seizures, and microcephaly (Kucera et al. 2015). The c.1981C>A, p.Pro66Thr variant is a novel missense variant in a gene that is missense intolerant (Z-score: 2.95). The amino acid residue is highly conserved among eukaryotes and is predicted to be damaging by in silico methods. There is one report of the allele in the public reference database, gnomAD, with no homozygous individuals, thus the variant is presumed rare. While there are no reports of this variant, other homozygous missense VARS variants have been linked to individuals with neurological findings including seizures, cortical atrophy, and microcephaly. Based on these lines of evidence, the variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.5	H
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.88		Gain of MoRF binding (P = 0.2988);
MVP		0.71
MPC		1.4
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.87
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.28		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1401228799; hg19: chr6-31750317;