11-3005379-T-C

Position:

• chr11-3005379-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CARS1 NM_001014437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30514914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS1	NM_001014437.3	c.2204A>G	p.Glu735Gly	missense_variant	20/23	ENST00000380525.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS1	ENST00000380525.9	c.2204A>G	p.Glu735Gly	missense_variant	20/23	1	NM_001014437.3	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The c.2204A>G (p.E735G) alteration is located in exon 20 (coding exon 20) of the CARS gene. This alteration results from a A to G substitution at nucleotide position 2204, causing the glutamic acid (E) at amino acid position 735 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.4	D;D;D;.
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.95, 0.97, 0.092	.;P;D;B
Vest4		0.35
MutPred		0.26		.;Gain of MoRF binding (P = 0.0585);Gain of MoRF binding (P = 0.0585);.;
MVP		0.72
MPC		0.47
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.31
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-3026609;