rs729662

Variant names:

• chr11-3006910-G-A
• rs729662
• NM_001014437.3:c.2118C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-3006910-G-A
• chr11-3006910-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001014437.3(CARS1):​c.2118C>T​(p.Pro706Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,298 control chromosomes in the GnomAD database, including 81,250 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (6752 hom., cov: 34)
  • Exomes 𝑓: 0.31 (74498 hom.)
• Consequence: CARS1 NM_001014437.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 37 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3	c.2118C>T	p.Pro706Pro	synonymous_variant	Exon 19 of 23	ENST00000380525.9	NP_001014437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9	c.2118C>T	p.Pro706Pro	synonymous_variant	Exon 19 of 23	1	NM_001014437.3	ENSP00000369897.4

Frequencies

GnomAD3 genomes AF: 0.260 AC: 39490 AN: 152140 Hom.: 6740 Cov.: 34

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.481

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.360

Gnomad EAS AF: 0.630

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.222

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.350 AC: 87746 AN: 251038 AF XY: 0.346

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.630

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.339

GnomAD4 exome AF: 0.305 AC: 446304 AN: 1461040 Hom.: 74498 Cov.: 35 AF XY: 0.307 AC XY: 223333 AN XY: 726846

African (AFR) AF: 0.0636 AC: 2129 AN: 33474

American (AMR) AF: 0.553 AC: 24741 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 9071 AN: 26130

East Asian (EAS) AF: 0.647 AC: 25698 AN: 39698

South Asian (SAS) AF: 0.385 AC: 33156 AN: 86220

European-Finnish (FIN) AF: 0.226 AC: 12062 AN: 53318

Middle Eastern (MID) AF: 0.333 AC: 1919 AN: 5768

European-Non Finnish (NFE) AF: 0.287 AC: 318668 AN: 1111364

Other (OTH) AF: 0.312 AC: 18860 AN: 60362

GnomAD4 genome AF: 0.260 AC: 39511 AN: 152258 Hom.: 6752 Cov.: 34 AF XY: 0.264 AC XY: 19624 AN XY: 74452

African (AFR) AF: 0.0738 AC: 3067 AN: 41566

American (AMR) AF: 0.438 AC: 6699 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 1250 AN: 3470

East Asian (EAS) AF: 0.630 AC: 3255 AN: 5166

South Asian (SAS) AF: 0.403 AC: 1945 AN: 4826

European-Finnish (FIN) AF: 0.222 AC: 2359 AN: 10614

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.291 AC: 19773 AN: 67998

Other (OTH) AF: 0.300 AC: 635 AN: 2114

Alfa AF: 0.289 Hom.: 12102

Bravo AF: 0.268

Asia WGS AF: 0.495 AC: 1719 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.306

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.62
DANN	Benign	0.60
PhyloP100		-1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs729662; hg19: chr11-3028140; COSMIC: COSV53449592;