11-3015797-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

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 (★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (1 hom.)
• Consequence: CARS1 NM_001014437.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.941

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]

ACMG classification

Verdict is Benign. Variant got -8 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 criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CARS1	NM_001014437.3	c.1970C>T	p.Pro657Leu	missense_variant	17/23	ENST00000380525.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARS1	ENST00000380525.9	c.1970C>T	p.Pro657Leu	missense_variant	17/23	1	NM_001014437.3	P3

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152226 Hom.: 0 Cov.: 32

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: 65 AN: 251404 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135900

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.: 1 Cov.: 31 AF XY: 0.0000756 AC XY: 55 AN XY: 727220

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.: 0 Cov.: 32 AF XY: 0.000819 AC XY: 61 AN XY: 74510

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.: 0

Bravo AF: 0.000960

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CARS1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 22, 2023

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	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	14
Dann	Benign	0.41
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.17	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.36	T
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	T
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

Other links and lift over

dbSNP: rs114985608; hg19: chr11-3037027;