Genetic Variant VARS1:p.Arg1199Pro (chr6-31779097-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006295.3(VARS1):c.3596G>C(p.Arg1199Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,532 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1199Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VARS1
NM_006295.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

Publications

0 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.3596G>C	p.Arg1199Pro	missense	Exon 29 of 30	NP_006286.1	P26640-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
VARS1	ENST00000375663.8	TSL:1 MANE Select	c.3596G>C	p.Arg1199Pro	missense	Exon 29 of 30	ENSP00000364815.3	P26640-1
VARS1	ENST00000851851.1		c.3641G>C	p.Arg1214Pro	missense	Exon 29 of 30	ENSP00000521910.1
VARS1	ENST00000851849.1		c.3635G>C	p.Arg1212Pro	missense	Exon 29 of 30	ENSP00000521908.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458532

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25970

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86012

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52080

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110968

Other (OTH)

AF:

0.00

AC:

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

Eigen

Benign

0.087

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.66

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PhyloP100

1.5

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.18

Sift

Benign

0.050

Sift4G

Benign

0.15

Polyphen

0.95

Vest4

0.68

MutPred

0.45

Loss of MoRF binding (P = 0.0025)

MVP

0.32

MPC

1.1

ClinPred

0.92

GERP RS

5.2

Varity_R

0.51

gMVP

0.87

Mutation Taster

=62/38

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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