11-3006944-T-C

Variant names:

• chr11-3006944-T-C
• rs145985522
• NM_001014437.3:c.2084A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001014437.3(CARS1):​c.2084A>G​(p.Gln695Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,613,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: CARS1 NM_001014437.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11617431).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000348 (53/152242) while in subpopulation AMR AF = 0.00196 (30/15288). AF 95% confidence interval is 0.00141. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2084A>G	p.Gln695Arg	missense	Exon 19 of 23	NP_001014437.1	P49589-3
	CARS1	NM_001194997.2		c.2084A>G	p.Gln695Arg	missense	Exon 19 of 23	NP_001181926.1
	CARS1	NM_001751.6		c.1835A>G	p.Gln612Arg	missense	Exon 18 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.2084A>G	p.Gln695Arg	missense	Exon 19 of 23	ENSP00000369897.4	P49589-3
	CARS1	ENST00000397111.9	TSL:1	c.1835A>G	p.Gln612Arg	missense	Exon 18 of 22	ENSP00000380300.5	P49589-1
	CARS1	ENST00000278224.13	TSL:1	c.1835A>G	p.Gln612Arg	missense	Exon 18 of 22	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000391 AC: 98 AN: 250960 AF XY: 0.000472

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000400 AC: 584 AN: 1461672 Hom.: 0 Cov.: 33 AF XY: 0.000414 AC XY: 301 AN XY: 727140

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.000425 AC: 19 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.000449 AC: 499 AN: 1111956

Other (OTH) AF: 0.000116 AC: 7 AN: 60392

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.000390 AC XY: 29 AN XY: 74376

African (AFR) AF: 0.0000723 AC: 3 AN: 41472

American (AMR) AF: 0.00196 AC: 30 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000545

EpiControl AF: 0.000652

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	0.072
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.044
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Uncertain	0.016	D
Sift4G	Benign	0.10	T
Polyphen		0.40	B
Vest4		0.17
MVP		0.63
MPC		0.26
ClinPred		0.042	T
GERP RS		4.7
Varity_R		0.16
gMVP		0.45
Mutation Taster		=81/19	polymorphism

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: rs145985522; hg19: chr11-3028174;