Genetic Variant DARS1:c.504+123C>T (chr2-135933787-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001349.4(DARS1):c.504+123C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,313,942 control chromosomes in the GnomAD database, including 206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 113 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 93 hom. )

Consequence

DARS1
NM_001349.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.853

Publications

1 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 Gene-Disease associations (from GenCC):

hypomyelination with brain stem and spinal cord involvement and leg spasticity
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

DARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-135933787-G-A is Benign according to our data. Variant chr2-135933787-G-A is described in ClinVar as Benign. ClinVar VariationId is 1327258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	NM_001349.4	MANE Select	c.504+123C>T		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.204+123C>T		intron	N/A	NP_001280241.1	P14868-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DARS1	ENST00000264161.9	TSL:1 MANE Select	c.504+123C>T	intron	N/A	ENSP00000264161.4	P14868-1
DARS1	ENST00000952144.1		c.504+123C>T	intron	N/A	ENSP00000622203.1
DARS1	ENST00000952145.1		c.504+123C>T	intron	N/A	ENSP00000622204.1

Frequencies

GnomAD3 genomes

AF:

0.0232

AC:

3529

AN:

152170

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0786

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00935

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0132

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.0153

GnomAD4 exome

AF:

0.00266

AC:

3093

AN:

1161654

Hom.:

AF XY:

0.00253

AC XY:

1406

AN XY:

556372

show subpopulations

African (AFR)

AF:

0.0884

AC:

2288

AN:

25890

American (AMR)

AF:

0.00613

AC:

AN:

13868

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

16526

East Asian (EAS)

AF:

0.0000323

AC:

AN:

30958

South Asian (SAS)

AF:

0.00810

AC:

283

AN:

34932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39326

Middle Eastern (MID)

AF:

0.00544

AC:

AN:

4226

European-Non Finnish (NFE)

AF:

0.0000790

AC:

AN:

949012

Other (OTH)

AF:

0.00584

AC:

274

AN:

46916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

140

281

421

562

702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0232

AC:

3538

AN:

152288

Hom.:

113

Cov.:

AF XY:

0.0229

AC XY:

1708

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0786

AC:

3265

AN:

41534

American (AMR)

AF:

0.00934

AC:

143

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.0132

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68024

Other (OTH)

AF:

0.0152

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

175

349

524

698

873

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0100

Hom.:

Bravo

AF:

0.0266

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.3

(source)

DANN

Benign

0.72

PhyloP100

0.85

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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