11-3055055-G-A

Variant names:

• chr11-3055055-G-A
• rs406598
• NM_001014437.3:c.25+2288C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001014437.3(CARS1):​c.25+2288C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 673,380 control chromosomes in the GnomAD database, including 56,769 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 0.33 (10234 hom., cov: 34)
  • Exomes 𝑓: 0.41 (46535 hom.)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 6 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	NM_001014437.3	MANE Select	c.25+2288C>T		intron	N/A	NP_001014437.1
	CARS1	NM_001194997.2		c.25+2288C>T		intron	N/A	NP_001181926.1
	CARS1	NM_001751.6		c.25+2288C>T		intron	N/A	NP_001742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	ENST00000380525.9	TSL:1 MANE Select	c.25+2288C>T		intron	N/A	ENSP00000369897.4
	CARS1	ENST00000397111.9	TSL:1	c.25+2288C>T		intron	N/A	ENSP00000380300.5
	CARS1	ENST00000278224.13	TSL:1	c.25+2288C>T		intron	N/A	ENSP00000278224.9

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49756 AN: 152052 Hom.: 10226 Cov.: 34

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.432

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.350

GnomAD4 exome AF: 0.410 AC: 213936 AN: 521210 Hom.: 46535 Cov.: 0 AF XY: 0.411 AC XY: 115996 AN XY: 282410

African (AFR) AF: 0.0804 AC: 1134 AN: 14098

American (AMR) AF: 0.549 AC: 14541 AN: 26488

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 7538 AN: 18390

East Asian (EAS) AF: 0.676 AC: 21533 AN: 31854

South Asian (SAS) AF: 0.413 AC: 23949 AN: 57976

European-Finnish (FIN) AF: 0.322 AC: 10482 AN: 32542

Middle Eastern (MID) AF: 0.395 AC: 1542 AN: 3908

European-Non Finnish (NFE) AF: 0.397 AC: 121843 AN: 306752

Other (OTH) AF: 0.389 AC: 11374 AN: 29202

GnomAD4 genome AF: 0.327 AC: 49772 AN: 152170 Hom.: 10234 Cov.: 34 AF XY: 0.329 AC XY: 24499 AN XY: 74376

African (AFR) AF: 0.0847 AC: 3518 AN: 41542

American (AMR) AF: 0.482 AC: 7377 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 1499 AN: 3472

East Asian (EAS) AF: 0.658 AC: 3407 AN: 5174

South Asian (SAS) AF: 0.430 AC: 2071 AN: 4816

European-Finnish (FIN) AF: 0.316 AC: 3338 AN: 10574

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27210 AN: 67982

Other (OTH) AF: 0.355 AC: 750 AN: 2112

Alfa AF: 0.342 Hom.: 1576

Bravo AF: 0.329

Asia WGS AF: 0.529 AC: 1838 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		0.31
Mutation Taster		=100/0	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: rs406598; hg19: chr11-3076285;