rs370805809

Variant names:

• chr2-135907390-T-A
• rs370805809
• NM_001349.4:c.1432A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-135907390-T-A
• chr2-135907390-T-C
• chr2-135907390-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001349.4(DARS1):​c.1432A>T​(p.Met478Leu) 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DARS1 NM_001349.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.1432A>T	p.Met478Leu	missense_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.1132A>T	p.Met378Leu	missense_variant	Exon 15 of 15		NP_001280241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.1432A>T	p.Met478Leu	missense_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4
DARS1	ENST00000422708.3	c.493A>T	p.Met165Leu	missense_variant	Exon 6 of 6	2		ENSP00000387508.1
DARS1	ENST00000478212.5	n.326A>T		non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5	n.681A>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;.
Vest4		0.70
MutPred		0.83		Loss of MoRF binding (P = 0.1151);.;
MVP		0.93
MPC		0.68
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.75
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370805809; hg19: chr2-136664960;