11-3039202-C-T

Position:

chr11-3039202-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_001014437.3(CARS1):c.643G>A(p.Ala215Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000952 in 1,607,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CARS1
NM_001014437.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.28

Variant links:

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 links:

CARS1-AS1 (HGNC:40125): (CARS1 antisense RNA 1)

CARS1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000144 (22/152338) while in subpopulation AMR AF= 0.000588 (9/15300). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARS1	NM_001014437.3 linkuse as main transcript	c.643G>A	p.Ala215Thr	missense_variant	6/23	ENST00000380525.9	NP_001014437.1
CARS1-AS1	NR_046580.1 linkuse as main transcript	n.2184-1578C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9 linkuse as main transcript	c.643G>A	p.Ala215Thr	missense_variant	6/23	1	NM_001014437.3	ENSP00000369897	P3	P49589-3
CARS1-AS1	ENST00000499962.1 linkuse as main transcript	n.2184-1578C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000172

AC:

AN:

250188

Hom.:

AF XY:

0.000148

AC XY:

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000656

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.0000900

AC:

131

AN:

1455532

Hom.:

Cov.:

AF XY:

0.0000745

AC XY:

AN XY:

724468

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000822

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.000144

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.000249

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2023

The c.643G>A (p.A215T) alteration is located in exon 6 (coding exon 6) of the CARS gene. This alteration results from a G to A substitution at nucleotide position 643, causing the alanine (A) at amino acid position 215 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

.;D;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

N;N;N;.

REVEL

Benign

0.25

Sift

Uncertain

0.0040

D;D;D;.

Sift4G

Uncertain

0.046

D;D;D;D

Polyphen

0.99, 0.99, 0.46

.;D;D;P

Vest4

0.72

MVP

0.69

MPC

0.82

ClinPred

0.29

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.22

gMVP

0.76

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over