NM_006295.3:c.3695C>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.55

Publications

2 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:

Y_RNA (HGNC:):

Y_RNA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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 link	c.3695C>A	p.Pro1232Gln	missense_variant	Exon 29 of 30	ENST00000375663.8	NP_006286.1	P26640-1A0A024RCN6
VARS1	XM_005249362.3 link	c.3698C>A	p.Pro1233Gln	missense_variant	Exon 29 of 30		XP_005249419.1
VARS1	XM_047419296.1 link	c.3698C>A	p.Pro1233Gln	missense_variant	Exon 28 of 29		XP_047275252.1
VARS1	XM_047419297.1 link	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	UniProt
VARS1	ENST00000375663.8 link	c.3695C>A	p.Pro1232Gln	missense_variant	Exon 29 of 30	1	NM_006295.3	ENSP00000364815.3	P26640-1
Y_RNA	ENST00000364685.1 link	n.-93C>A		upstream_gene_variant		6
VARS1	ENST00000463184.1 link	n.*232C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460694

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726648

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.4

PhyloP100

3.5

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.0

REVEL

Benign

0.20

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.014

Polyphen

1.0

Vest4

0.67

MutPred

0.36

Gain of MoRF binding (P = 0.0557);

MVP

0.41

MPC

1.3

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.32

gMVP

0.83

Mutation Taster

=26/74

disease causing

(source)

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

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NM_006295.3:c.3695C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over