chr11-3029392-G-A

Position:

• chr11-3029392-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001014437.3(CARS1):​c.853C>T​(p.Leu285Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,614,076 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0078 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (77 hom.)
• Consequence: CARS1 NM_001014437.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.911

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010881454).
• BP6: Variant 11-3029392-G-A is Benign according to our data. Variant chr11-3029392-G-A is described in ClinVar as [Benign]. Clinvar id is 731546.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00778 (1185/152350) while in subpopulation AMR AF= 0.0101 (154/15302). AF 95% confidence interval is 0.00936. There are 10 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CARS1	NM_001014437.3	c.853C>T	p.Leu285Phe	missense_variant	8/23	ENST00000380525.9	NP_001014437.1
CARS1-AS1	NR_046580.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CARS1	ENST00000380525.9	c.853C>T	p.Leu285Phe	missense_variant	8/23	1	NM_001014437.3	ENSP00000369897	P3
CARS1-AS1	ENST00000499962.1			upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00778 AC: 1185 AN: 152232 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0101

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00998

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00758 AC: 1906 AN: 251400 Hom.: 10 AF XY: 0.00769 AC XY: 1045 AN XY: 135874

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.00972

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000849

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.00945 AC: 13808 AN: 1461726 Hom.: 77 Cov.: 31 AF XY: 0.00923 AC XY: 6709 AN XY: 727182

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00853

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.0177

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00888

GnomAD4 genome AF: 0.00778 AC: 1185 AN: 152350 Hom.: 10 Cov.: 32 AF XY: 0.00862 AC XY: 642 AN XY: 74516

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.0101

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0216

Gnomad4 NFE AF: 0.00998

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00844 Hom.: 9

Bravo AF: 0.00641

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00780 AC: 947

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00932

EpiControl AF: 0.00759

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CARS1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.54
DANN	Benign	0.48
DEOGEN2	Benign	0.069	.;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.040	N
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.16	.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.53	N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.74	T;T;T;.
Sift4G	Benign	0.72	T;T;T;T
Polyphen		0.0, 0.0010	.;B;B;B
Vest4		0.16
MVP		0.21
MPC		0.26
ClinPred		0.0012	T
GERP RS		-3.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.018
gMVP		0.28

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: rs148335154; hg19: chr11-3050622;