Genetic Variant NM_001014437.3:c.2204A>G (chr11-3005379-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001014437.3(CARS1):c.2204A>G(p.Glu735Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E735D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

CARS1
NM_001014437.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Publications

0 publications found

Variant links:

Genes affected

CARS1 (HGNC:1493): (cysteinyl-tRNA synthetase 1) This gene encodes a class 1 aminoacyl-tRNA synthetase, cysteinyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. This gene is one of several located near the imprinted gene domain on chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2010]

CARS1 Gene-Disease associations (from GenCC):

microcephaly, developmental delay, and brittle hair syndrome
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

CARS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30514914).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARS1	NM_001014437.3	MANE Select	c.2204A>G	p.Glu735Gly	missense	Exon 20 of 23	NP_001014437.1	P49589-3
CARS1	NM_001194997.2		c.2204A>G	p.Glu735Gly	missense	Exon 20 of 23	NP_001181926.1
CARS1	NM_001751.6		c.1955A>G	p.Glu652Gly	missense	Exon 19 of 22	NP_001742.1	P49589-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CARS1	ENST00000380525.9	TSL:1 MANE Select	c.2204A>G	p.Glu735Gly	missense	Exon 20 of 23	ENSP00000369897.4	P49589-3
CARS1	ENST00000397111.9	TSL:1	c.1955A>G	p.Glu652Gly	missense	Exon 19 of 22	ENSP00000380300.5	P49589-1
CARS1	ENST00000278224.13	TSL:1	c.1955A>G	p.Glu652Gly	missense	Exon 19 of 22	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.023

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.33

MutationAssessor

Pathogenic

3.9

PhyloP100

5.8

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.4

REVEL

Benign

0.25

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0080

Polyphen

0.95

Vest4

0.35

MutPred

0.26

Gain of MoRF binding (P = 0.0585)

MVP

0.72

MPC

0.47

ClinPred

0.99

GERP RS

3.9

Varity_R

0.31

gMVP

0.49

Mutation Taster

=35/65

disease causing

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over