Genetic Variant NM_006295.3:c.2074G>C (chr6-31782361-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.23

Publications

1 publications found

Variant links:

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

VARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460300

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52234

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111836

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.92

MetaSVM

Benign

-0.49

MutationAssessor

Pathogenic

3.4

PhyloP100

4.2

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.67

MutPred

0.82

Gain of catalytic residue at A692 (P = 0.0439)

MVP

0.45

MPC

1.5

ClinPred

0.99

GERP RS

5.0

PromoterAI

-0.0040

Neutral

(source)

Varity_R

0.95

gMVP

0.97

Mutation Taster

=15/85

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over