11-3024421-T-C

Variant names:

• chr11-3024421-T-C
• rs438384
• NM_001014437.3:c.1153+2255A>G

Variant summary

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

The NM_001014437.3(CARS1):​c.1153+2255A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,926 control chromosomes in the GnomAD database, including 10,148 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 (10148 hom., cov: 32)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.294
• Publications: 8 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3	c.1153+2255A>G		intron_variant	Intron 10 of 22	ENST00000380525.9	NP_001014437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9	c.1153+2255A>G		intron_variant	Intron 10 of 22	1	NM_001014437.3	ENSP00000369897.4

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50167 AN: 151810 Hom.: 10137 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.627

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.354

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.330 AC: 50202 AN: 151926 Hom.: 10148 Cov.: 32 AF XY: 0.332 AC XY: 24650 AN XY: 74260

African (AFR) AF: 0.101 AC: 4164 AN: 41404

American (AMR) AF: 0.485 AC: 7403 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1492 AN: 3472

East Asian (EAS) AF: 0.627 AC: 3223 AN: 5138

South Asian (SAS) AF: 0.427 AC: 2057 AN: 4820

European-Finnish (FIN) AF: 0.308 AC: 3253 AN: 10572

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

European-Non Finnish (NFE) AF: 0.401 AC: 27253 AN: 67950

Other (OTH) AF: 0.358 AC: 755 AN: 2106

Alfa AF: 0.354 Hom.: 1619

Bravo AF: 0.334

Asia WGS AF: 0.507 AC: 1762 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.5
DANN	Benign	0.45
PhyloP100		0.29
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: rs438384; hg19: chr11-3045651;