NM_006295.3:c.3696G>C

Variant names:

• chr6-31778997-C-G
• NM_006295.3:c.3696G>C
• VARS1 p.Pro1232Pro

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_006295.3(VARS1):​c.3696G>C​(p.Pro1232Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P1232P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VARS1 NM_006295.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.532
• Publications: 0 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

Y_RNA (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP7: Synonymous conserved (PhyloP=0.532 with no splicing effect.

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.3696G>C	p.Pro1232Pro	synonymous	Exon 29 of 30	NP_006286.1	P26640-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VARS1	ENST00000375663.8	TSL:1 MANE Select	c.3696G>C	p.Pro1232Pro	synonymous	Exon 29 of 30	ENSP00000364815.3	P26640-1
	VARS1	ENST00000851851.1		c.3741G>C	p.Pro1247Pro	synonymous	Exon 29 of 30	ENSP00000521910.1
	VARS1	ENST00000851849.1		c.3735G>C	p.Pro1245Pro	synonymous	Exon 29 of 30	ENSP00000521908.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	8.6
DANN	Benign	0.63
PhyloP100		0.53

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr6-31746774;