rs1308917228

Variant names:

• chr11-3005379-T-A
• rs1308917228
• NM_001014437.3:c.2204A>T

Your query was ambiguous. Multiple possible variants found:

• chr11-3005379-T-A
• chr11-3005379-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001014437.3(CARS1):​c.2204A>T​(p.Glu735Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E735D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CARS1 NM_001014437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.79
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33743575).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	NM_001014437.3	MANE Select	c.2204A>T	p.Glu735Val	missense	Exon 20 of 23	NP_001014437.1	P49589-3
	CARS1	NM_001194997.2		c.2204A>T	p.Glu735Val	missense	Exon 20 of 23	NP_001181926.1
	CARS1	NM_001751.6		c.1955A>T	p.Glu652Val	missense	Exon 19 of 22	NP_001742.1	P49589-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	ENST00000380525.9	TSL:1 MANE Select	c.2204A>T	p.Glu735Val	missense	Exon 20 of 23	ENSP00000369897.4	P49589-3
	CARS1	ENST00000397111.9	TSL:1	c.1955A>T	p.Glu652Val	missense	Exon 19 of 22	ENSP00000380300.5	P49589-1
	CARS1	ENST00000278224.13	TSL:1	c.1955A>T	p.Glu652Val	missense	Exon 19 of 22	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251244 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460448 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 726600

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110804

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Benign	0.26
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.95	P
Vest4		0.41
MutPred		0.27		Gain of MoRF binding (P = 0.0506)
MVP		0.70
MPC		0.32
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.47
gMVP		0.53
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1308917228; hg19: chr11-3026609;