chr11-3046876-G-A

Variant names:

• chr11-3046876-G-A
• rs7111857
• NM_001014437.3:c.274+877C>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.274+877C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 151,996 control chromosomes in the GnomAD database, including 12,902 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 0.41 (12902 hom., cov: 32)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.65
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3	c.274+877C>T		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.274+877C>T		intron_variant	Intron 2 of 22	1	NM_001014437.3	ENSP00000369897.4

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61755 AN: 151876 Hom.: 12898 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.388

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

GnomAD4 genome AF: 0.407 AC: 61798 AN: 151996 Hom.: 12902 Cov.: 32 AF XY: 0.408 AC XY: 30294 AN XY: 74280

African (AFR) AF: 0.453 AC: 18781 AN: 41450

American (AMR) AF: 0.346 AC: 5274 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1284 AN: 3464

East Asian (EAS) AF: 0.199 AC: 1030 AN: 5164

South Asian (SAS) AF: 0.396 AC: 1913 AN: 4828

European-Finnish (FIN) AF: 0.473 AC: 4997 AN: 10556

Middle Eastern (MID) AF: 0.401 AC: 118 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27229 AN: 67958

Other (OTH) AF: 0.386 AC: 815 AN: 2110

Alfa AF: 0.320 Hom.: 1218

Bravo AF: 0.397

Asia WGS AF: 0.314 AC: 1092 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.68
PhyloP100		-3.6
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: rs7111857; hg19: chr11-3068106;