Genetic Variant NM_001014437.3:c.2118C>T (chr11-3006910-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001014437.3(CARS1):c.2118C>T(p.Pro706Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 1,613,298 control chromosomes in the GnomAD database, including 81,250 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 6752 hom., cov: 34)

Exomes 𝑓: 0.31 ( 74498 hom. )

Consequence

CARS1
NM_001014437.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.85

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

microcephaly, developmental delay, and brittle hair syndrome
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

CARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP7

Synonymous conserved (PhyloP=-1.85 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CARS1	NM_001014437.3 link	c.2118C>T	p.Pro706Pro	synonymous_variant	Exon 19 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.2118C>T	p.Pro706Pro	synonymous_variant	Exon 19 of 23	1	NM_001014437.3	ENSP00000369897.4		P49589-3

Frequencies

GnomAD3 genomes

AF:

0.260

AC:

39490

AN:

152140

Hom.:

6740

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0739

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.360

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.222

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.294

GnomAD2 exomes

AF:

0.350

AC:

87746

AN:

251038

AF XY:

0.346

show subpopulations

Gnomad AFR exome

AF:

0.0667

Gnomad AMR exome

AF:

0.573

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.630

Gnomad FIN exome

AF:

0.221

Gnomad NFE exome

AF:

0.292

Gnomad OTH exome

AF:

0.339

GnomAD4 exome

AF:

0.305

AC:

446304

AN:

1461040

Hom.:

74498

Cov.:

AF XY:

0.307

AC XY:

223333

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.0636

AC:

2129

AN:

33474

American (AMR)

AF:

0.553

AC:

24741

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.347

AC:

9071

AN:

26130

East Asian (EAS)

AF:

0.647

AC:

25698

AN:

39698

South Asian (SAS)

AF:

0.385

AC:

33156

AN:

86220

European-Finnish (FIN)

AF:

0.226

AC:

12062

AN:

53318

Middle Eastern (MID)

AF:

0.333

AC:

1919

AN:

5768

European-Non Finnish (NFE)

AF:

0.287

AC:

318668

AN:

1111364

Other (OTH)

AF:

0.312

AC:

18860

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

15210

30421

45631

60842

76052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10824

21648

32472

43296

54120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.260

AC:

39511

AN:

152258

Hom.:

6752

Cov.:

AF XY:

0.264

AC XY:

19624

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0738

AC:

3067

AN:

41566

American (AMR)

AF:

0.438

AC:

6699

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.360

AC:

1250

AN:

3470

East Asian (EAS)

AF:

0.630

AC:

3255

AN:

5166

South Asian (SAS)

AF:

0.403

AC:

1945

AN:

4826

European-Finnish (FIN)

AF:

0.222

AC:

2359

AN:

10614

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.291

AC:

19773

AN:

67998

Other (OTH)

AF:

0.300

AC:

635

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1425

2851

4276

5702

7127

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

410

820

1230

1640

2050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.289

Hom.:

12102

Bravo

AF:

0.268

Asia WGS

AF:

0.495

AC:

1719

AN:

3478

EpiCase

AF:

0.298

EpiControl

AF:

0.306

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

0.62

(source)

DANN

Benign

0.60

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over