11-3015797-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001014437.3(CARS1):c.1970C>T(p.Pro657Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,614,186 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 1 hom. )

Consequence

CARS1
NM_001014437.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.941

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.005415261).

BP6

Variant 11-3015797-G-A is Benign according to our data. Variant chr11-3015797-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3055169.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00084 (128/152344) while in subpopulation AFR AF= 0.00301 (125/41578). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 61 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3 link	c.1970C>T	p.Pro657Leu	missense_variant	Exon 17 of 23	ENST00000380525.9	NP_001014437.1	P49589-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9 link	c.1970C>T	p.Pro657Leu	missense_variant	Exon 17 of 23	1	NM_001014437.3	ENSP00000369897.4		P49589-3

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000259

AC:

AN:

251404

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00351

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1461842

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.00296

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152344

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00301

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.000960

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000305

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CARS1-related disorder

Benign:1

Sep 22, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.41

DEOGEN2

Benign

0.10

.;T;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.17

M_CAP

Benign

0.013

MetaRNN

Benign

0.0054

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;L;L;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.2

N;N;N;.

REVEL

Benign

0.014

Sift

Benign

0.21

T;T;T;.

Sift4G

Benign

0.23

T;T;T;T

Polyphen

0.0020, 0.017

.;B;B;B

Vest4

0.20

MVP

0.48

MPC

0.25

ClinPred

0.0059

GERP RS

1.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.015

gMVP

0.25

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