Genetic Variant DARS1:c.-134G>A (chr2-135985602-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001349.4(DARS1):c.-134G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,524,210 control chromosomes in the GnomAD database, including 431 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 0.029 ( 77 hom., cov: 33)

Exomes 𝑓: 0.019 ( 354 hom. )

Consequence

DARS1
NM_001349.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.254

Publications

6 publications found

Variant links:

Genes affected

DARS1 (HGNC:2678): (aspartyl-tRNA synthetase 1) This gene encodes a member of a multienzyme complex that functions in mediating the attachment of amino acids to their cognate tRNAs. The encoded protein ligates L-aspartate to tRNA(Asp). Mutations in this gene have been found in patients showing hypomyelination with brainstem and spinal cord involvement and leg spasticity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

DARS1 links:

DARS1-AS1 (HGNC:40170): (DARS1 antisense RNA 1)

DARS1-AS1 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=-0.64).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	NM_001349.4	MANE Select	c.-134G>A	5_prime_UTR	Exon 1 of 16	NP_001340.2
DARS1	NM_001293312.1		c.-376G>A	5_prime_UTR	Exon 1 of 15	NP_001280241.1	P14868-2
DARS1-AS1	NR_110199.1		n.341+86C>T	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	ENST00000264161.9	TSL:1 MANE Select	c.-134G>A	5_prime_UTR	Exon 1 of 16	ENSP00000264161.4	P14868-1
DARS1	ENST00000952144.1		c.-134G>A	5_prime_UTR	Exon 1 of 16	ENSP00000622203.1
DARS1	ENST00000952145.1		c.-134G>A	5_prime_UTR	Exon 1 of 16	ENSP00000622204.1

Frequencies

GnomAD3 genomes

AF:

0.0286

AC:

4348

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0385

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0279

Gnomad ASJ

AF:

0.0409

Gnomad EAS

AF:

0.0594

Gnomad SAS

AF:

0.0166

Gnomad FIN

AF:

0.0223

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0287

GnomAD2 exomes

AF:

0.0279

AC:

3921

AN:

140644

AF XY:

0.0265

show subpopulations

Gnomad AFR exome

AF:

0.0433

Gnomad AMR exome

AF:

0.0338

Gnomad ASJ exome

AF:

0.0390

Gnomad EAS exome

AF:

0.0549

Gnomad FIN exome

AF:

0.0245

Gnomad NFE exome

AF:

0.0222

Gnomad OTH exome

AF:

0.0291

GnomAD4 exome

AF:

0.0192

AC:

26322

AN:

1371924

Hom.:

354

Cov.:

AF XY:

0.0195

AC XY:

13109

AN XY:

673836

show subpopulations

African (AFR)

AF:

0.0404

AC:

1263

AN:

31298

American (AMR)

AF:

0.0300

AC:

945

AN:

31518

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

834

AN:

23136

East Asian (EAS)

AF:

0.0546

AC:

1983

AN:

36348

South Asian (SAS)

AF:

0.0159

AC:

1242

AN:

77894

European-Finnish (FIN)

AF:

0.0227

AC:

1077

AN:

47450

Middle Eastern (MID)

AF:

0.0315

AC:

173

AN:

5500

European-Non Finnish (NFE)

AF:

0.0164

AC:

17442

AN:

1062200

Other (OTH)

AF:

0.0241

AC:

1363

AN:

56580

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1359

2718

4078

5437

6796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.0286

AC:

4357

AN:

152286

Hom.:

Cov.:

AF XY:

0.0286

AC XY:

2127

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0384

AC:

1597

AN:

41582

American (AMR)

AF:

0.0281

AC:

430

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0409

AC:

142

AN:

3472

East Asian (EAS)

AF:

0.0597

AC:

308

AN:

5156

South Asian (SAS)

AF:

0.0166

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0223

AC:

237

AN:

10616

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0219

AC:

1486

AN:

68002

Other (OTH)

AF:

0.0293

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

208

416

624

832

1040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0260

Hom.:

Bravo

AF:

0.0294

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.6

(source)

DANN

Benign

0.92

PhyloP100

0.25

PromoterAI

0.16

Neutral

(source)

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over