chr6-31782361-C-G

Variant names:

• chr6-31782361-C-G
• rs747824231
• NM_006295.3:c.2074G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_006295.3(VARS1):​c.2074G>C​(p.Ala692Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,300 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: VARS1 NM_006295.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.23
• Publications: 1 publications found

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]

VARS1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• combined oxidative phosphorylation defect type 20

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 6-31782361-C-G is Pathogenic according to our data. Variant chr6-31782361-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 520392.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006295.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS1	NM_006295.3	MANE Select	c.2074G>C	p.Ala692Pro	missense	Exon 17 of 30	NP_006286.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS1	ENST00000375663.8	TSL:1 MANE Select	c.2074G>C	p.Ala692Pro	missense	Exon 17 of 30	ENSP00000364815.3
	VARS1	ENST00000851851.1		c.2074G>C	p.Ala692Pro	missense	Exon 17 of 30	ENSP00000521910.1
	VARS1	ENST00000851849.1		c.2113G>C	p.Ala705Pro	missense	Exon 17 of 30	ENSP00000521908.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460300 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726462

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111836

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with microcephaly, seizures, and cortical atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		4.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.82		Gain of catalytic residue at A692 (P = 0.0439)
MVP		0.45
MPC		1.5
ClinPred		0.99	D
GERP RS		5.0
PromoterAI		-0.0040	Neutral
Varity_R		0.95
gMVP		0.97
Mutation Taster		=15/85	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs747824231; hg19: chr6-31750138;