11-3001989-T-C

Position:

• chr11-3001989-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001014437.3(CARS1):​c.2342A>G​(p.Tyr781Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 4.93

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARS1	NM_001014437.3	c.2342A>G	p.Tyr781Cys	missense_variant	22/23	ENST00000380525.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS1	ENST00000380525.9	c.2342A>G	p.Tyr781Cys	missense_variant	22/23	1	NM_001014437.3	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Nov 01, 2022

The c.2342A>G (p.Y781C) alteration is located in exon 22 (coding exon 22) of the CARS gene. This alteration results from a A to G substitution at nucleotide position 2342, causing the tyrosine (Y) at amino acid position 781 to be replaced by a cysteine (C). 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	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	4.1	.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.6	D;D;D;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0, 1.0, 1.0	.;D;D;D
Vest4		0.94
MutPred		0.38		.;Loss of phosphorylation at Y698 (P = 0.0059);Loss of phosphorylation at Y698 (P = 0.0059);.;
MVP		0.87
MPC		0.99
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.83
gMVP		0.69

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: chr11-3023219;