rs886037635

chr2-135922829-T-Cchr2-135922829-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001349.4(DARS1):c.766A>G(p.Met256Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. M256L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DARS1 NM_001349.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.97

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-135922829-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 50988.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS1	NM_001349.4	c.766A>G	p.Met256Val	missense_variant	9/16	ENST00000264161.9
DARS1	NM_001293312.1	c.466A>G	p.Met156Val	missense_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS1	ENST00000264161.9	c.766A>G	p.Met256Val	missense_variant	9/16	1	NM_001349.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.87
MutPred		0.65		Loss of helix (P = 0.2662);
MVP		0.71
MPC		0.67
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs886037635; hg19: chr2-136680399;