2-135907405-A-T

Variant names:

• chr2-135907405-A-T
• rs76296777
• NM_001349.4:c.1417T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001349.4(DARS1):​c.1417T>A​(p.Leu473Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. 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, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.60

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.1417T>A	p.Leu473Met	missense_variant, splice_region_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.1117T>A	p.Leu373Met	missense_variant, splice_region_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.1417T>A	p.Leu473Met	missense_variant, splice_region_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4
DARS1	ENST00000422708.3	c.478T>A	p.Leu160Met	missense_variant, splice_region_variant	Exon 6 of 6	2		ENSP00000387508.1
DARS1	ENST00000478212.5	n.311T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5	n.666T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;T
Eigen	Benign	0.045
Eigen_PC	Benign	-0.0048
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.9	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.29	N;N
REVEL	Uncertain	0.51
Sift	Benign	0.14	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.71	P;.
Vest4		0.57
MutPred		0.73		Loss of catalytic residue at L473 (P = 0.0134);.;
MVP		0.75
MPC		0.43
ClinPred		0.62	D
GERP RS		3.0
Varity_R		0.38
gMVP		0.75

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: rs76296777; hg19: chr2-136664975;