11-3044070-G-C

Variant names:

• chr11-3044070-G-C
• rs375579
• NM_001014437.3:c.275-1814C>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.275-1814C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 152,004 control chromosomes in the GnomAD database, including 10,296 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 (10296 hom., cov: 31)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69
• Publications: 4 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.639 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3	c.275-1814C>G		intron_variant	Intron 2 of 22	ENST00000380525.9	NP_001014437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9	c.275-1814C>G		intron_variant	Intron 2 of 22	1	NM_001014437.3	ENSP00000369897.4

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49945 AN: 151886 Hom.: 10288 Cov.: 31

Gnomad AFR AF: 0.0862

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.483

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.658

Gnomad SAS AF: 0.431

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.352

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

GnomAD4 genome AF: 0.329 AC: 49961 AN: 152004 Hom.: 10296 Cov.: 31 AF XY: 0.331 AC XY: 24567 AN XY: 74304

African (AFR) AF: 0.0861 AC: 3571 AN: 41494

American (AMR) AF: 0.484 AC: 7394 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3468

East Asian (EAS) AF: 0.658 AC: 3384 AN: 5146

South Asian (SAS) AF: 0.429 AC: 2068 AN: 4816

European-Finnish (FIN) AF: 0.317 AC: 3345 AN: 10554

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

European-Non Finnish (NFE) AF: 0.403 AC: 27352 AN: 67942

Other (OTH) AF: 0.357 AC: 754 AN: 2110

Alfa AF: 0.201 Hom.: 464

Bravo AF: 0.331

Asia WGS AF: 0.521 AC: 1812 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.24
DANN	Benign	0.49
PhyloP100		-1.7
RBP_binding_hub_radar		0.67
RBP_regulation_power_radar		2.0
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: rs375579; hg19: chr11-3065300; COSMIC: COSV53460966; COSMIC: COSV53460966;