11-3017133-G-T

Variant names:

• chr11-3017133-G-T
• rs61737274
• NM_001014437.3:c.1890C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001014437.3(CARS1):​c.1890C>A​(p.Ile630Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00419 in 1,614,024 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (126 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (122 hom.)
• Consequence: CARS1 NM_001014437.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0220
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 11-3017133-G-T is Benign according to our data. Variant chr11-3017133-G-T is described in ClinVar as Benign. ClinVar VariationId is 779130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.022 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0743 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARS1	NM_001014437.3	MANE Select	c.1890C>A	p.Ile630Ile	synonymous	Exon 16 of 23	NP_001014437.1	P49589-3
	CARS1	NM_001194997.2		c.1890C>A	p.Ile630Ile	synonymous	Exon 16 of 23	NP_001181926.1
	CARS1	NM_001751.6		c.1641C>A	p.Ile547Ile	synonymous	Exon 15 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.1890C>A	p.Ile630Ile	synonymous	Exon 16 of 23	ENSP00000369897.4	P49589-3
	CARS1	ENST00000397111.9	TSL:1	c.1641C>A	p.Ile547Ile	synonymous	Exon 15 of 22	ENSP00000380300.5	P49589-1
	CARS1	ENST00000278224.13	TSL:1	c.1641C>A	p.Ile547Ile	synonymous	Exon 15 of 22	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3367 AN: 152138 Hom.: 126 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00567 AC: 1424 AN: 251246 AF XY: 0.00400

Gnomad AFR exome AF: 0.0768

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00232 AC: 3391 AN: 1461768 Hom.: 122 Cov.: 31 AF XY: 0.00198 AC XY: 1440 AN XY: 727188

African (AFR) AF: 0.0792 AC: 2650 AN: 33470

American (AMR) AF: 0.00427 AC: 191 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.000191 AC: 212 AN: 1111928

Other (OTH) AF: 0.00498 AC: 301 AN: 60382

GnomAD4 genome AF: 0.0221 AC: 3371 AN: 152256 Hom.: 126 Cov.: 32 AF XY: 0.0217 AC XY: 1615 AN XY: 74440

African (AFR) AF: 0.0765 AC: 3178 AN: 41526

American (AMR) AF: 0.00889 AC: 136 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68018

Other (OTH) AF: 0.0142 AC: 30 AN: 2114

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.0254

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.0
DANN	Benign	0.87
PhyloP100		-0.022
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
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: rs61737274; hg19: chr11-3038363;