Genetic Variant CARS1:c.1153+2255A>G (chr11-3024421-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001014437.3(CARS1):c.1153+2255A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 151,926 control chromosomes in the GnomAD database, including 10,148 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 0.33 ( 10148 hom., cov: 32)

Consequence

CARS1
NM_001014437.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.294

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001014437.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CARS1	NM_001014437.3	MANE Select	c.1153+2255A>G	intron	N/A	NP_001014437.1	P49589-3
CARS1	NM_001194997.2		c.1153+2255A>G	intron	N/A	NP_001181926.1
CARS1	NM_001751.6		c.904+2255A>G	intron	N/A	NP_001742.1	P49589-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CARS1	ENST00000380525.9	TSL:1 MANE Select	c.1153+2255A>G	intron	N/A	ENSP00000369897.4	P49589-3
CARS1	ENST00000397111.9	TSL:1	c.904+2255A>G	intron	N/A	ENSP00000380300.5	P49589-1
CARS1	ENST00000278224.13	TSL:1	c.904+2255A>G	intron	N/A	ENSP00000278224.9	P49589-2

Frequencies

GnomAD3 genomes

AF:

0.330

AC:

50167

AN:

151810

Hom.:

10137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.100

Gnomad AMI

AF:

0.544

Gnomad AMR

AF:

0.484

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.627

Gnomad SAS

AF:

0.428

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.401

Gnomad OTH

AF:

0.354

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.330

AC:

50202

AN:

151926

Hom.:

10148

Cov.:

AF XY:

0.332

AC XY:

24650

AN XY:

74260

show subpopulations

African (AFR)

AF:

0.101

AC:

4164

AN:

41404

American (AMR)

AF:

0.485

AC:

7403

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1492

AN:

3472

East Asian (EAS)

AF:

0.627

AC:

3223

AN:

5138

South Asian (SAS)

AF:

0.427

AC:

2057

AN:

4820

European-Finnish (FIN)

AF:

0.308

AC:

3253

AN:

10572

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.401

AC:

27253

AN:

67950

Other (OTH)

AF:

0.358

AC:

755

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1539

3077

4616

6154

7693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

502

1004

1506

2008

2510

<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:

0.354

Hom.:

1619

Bravo

AF:

0.334

Asia WGS

AF:

0.507

AC:

1762

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

2.5

(source)

DANN

Benign

0.45

PhyloP100

0.29

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over