11-3025068-C-T

Variant names:

• chr11-3025068-C-T
• rs377765
• NM_001014437.3:c.1153+1608G>A

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+1608G>A 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 152,012 control chromosomes in the GnomAD database, including 10,153 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 (10153 hom., cov: 32)
• Consequence: CARS1 NM_001014437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.611
• 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 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.1153+1608G>A		intron	N/A	NP_001014437.1
	CARS1	NM_001194997.2		c.1153+1608G>A		intron	N/A	NP_001181926.1
	CARS1	NM_001751.6		c.904+1608G>A		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.1153+1608G>A		intron	N/A	ENSP00000369897.4
	CARS1	ENST00000397111.9	TSL:1	c.904+1608G>A		intron	N/A	ENSP00000380300.5
	CARS1	ENST00000278224.13	TSL:1	c.904+1608G>A		intron	N/A	ENSP00000278224.9

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50165 AN: 151896 Hom.: 10142 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.546

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.330 AC: 50200 AN: 152012 Hom.: 10153 Cov.: 32 AF XY: 0.332 AC XY: 24667 AN XY: 74294

African (AFR) AF: 0.100 AC: 4163 AN: 41472

American (AMR) AF: 0.485 AC: 7398 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1493 AN: 3472

East Asian (EAS) AF: 0.628 AC: 3251 AN: 5174

South Asian (SAS) AF: 0.427 AC: 2053 AN: 4810

European-Finnish (FIN) AF: 0.308 AC: 3250 AN: 10556

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.401 AC: 27234 AN: 67956

Other (OTH) AF: 0.358 AC: 756 AN: 2110

Alfa AF: 0.359 Hom.: 5104

Bravo AF: 0.334

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.1
DANN	Benign	0.84
PhyloP100		0.61
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: rs377765; hg19: chr11-3046298;