dbSNP rs532864330: DARS1:p.Arg81Leu (chr2-135961474-C-A) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_001349.4(DARS1):c.242G>T(p.Arg81Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 1,359,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R81H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

DARS1
NM_001349.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

DARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 0.74697 (below the threshold of 3.09). Trascript score misZ: 0.93713 (below the threshold of 3.09). GenCC associations: The gene is linked to hypomyelination with brain stem and spinal cord involvement and leg spasticity.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4 link	c.242G>T	p.Arg81Leu	missense_variant	Exon 4 of 16	ENST00000264161.9	NP_001340.2	P14868-1A0A140VJW5
DARS1	NM_001293312.1 link	c.-59G>T		5_prime_UTR_variant	Exon 3 of 15		NP_001280241.1	P14868-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9 link	c.242G>T	p.Arg81Leu	missense_variant	Exon 4 of 16	1	NM_001349.4	ENSP00000264161.4		P14868-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000147

AC:

AN:

1359334

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

681804

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31494

American (AMR)

AF:

0.00

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25516

East Asian (EAS)

AF:

0.00

AC:

AN:

39274

South Asian (SAS)

AF:

0.00

AC:

AN:

84194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.00000196

AC:

AN:

1018276

Other (OTH)

AF:

0.00

AC:

AN:

57042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.067

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

-0.085

MutationAssessor

Pathogenic

3.6

H;.;.;.

PhyloP100

7.6

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-6.9

D;D;D;D

REVEL

Pathogenic

0.69

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;.;.

Polyphen

1.0

D;.;.;.

Vest4

0.91

MutPred

0.82

Loss of MoRF binding (P = 0.0145);.;.;.;

MVP

0.67

MPC

0.79

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.82

Mutation Taster

=6/94

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over