6-31778998-G-T

Variant names:

• chr6-31778998-G-T
• rs1472868752
• NM_006295.3:c.3695C>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006295.3(VARS1):​c.3695C>A​(p.Pro1232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,694 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1232P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.55

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]

Y_RNA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VARS1	NM_006295.3	c.3695C>A	p.Pro1232Gln	missense_variant	Exon 29 of 30	ENST00000375663.8	NP_006286.1
VARS1	XM_005249362.3	c.3698C>A	p.Pro1233Gln	missense_variant	Exon 29 of 30		XP_005249419.1
VARS1	XM_047419296.1	c.3698C>A	p.Pro1233Gln	missense_variant	Exon 28 of 29		XP_047275252.1
VARS1	XM_047419297.1	c.3695C>A	p.Pro1232Gln	missense_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.3695C>A	p.Pro1232Gln	missense_variant	Exon 29 of 30	1	NM_006295.3	ENSP00000364815.3
Y_RNA	ENST00000364685.1	n.-93C>A		upstream_gene_variant		6
VARS1	ENST00000463184.1	n.*232C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460694 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726648

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

-

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.019	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.36		Gain of MoRF binding (P = 0.0557);
MVP		0.41
MPC		1.3
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.32
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1472868752; hg19: chr6-31746775;