2-135907336-G-T

Variant names:

• chr2-135907336-G-T
• rs1020492946
• NM_001349.4:c.1486C>A

Variant summary

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

The NM_001349.4(DARS1):​c.1486C>A​(p.Pro496Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,454,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DARS1 NM_001349.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.72

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, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.1486C>A	p.Pro496Thr	missense_variant	Exon 16 of 16	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.1186C>A	p.Pro396Thr	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.1486C>A	p.Pro496Thr	missense_variant	Exon 16 of 16	1	NM_001349.4	ENSP00000264161.4
DARS1	ENST00000422708.3	c.547C>A	p.Pro183Thr	missense_variant	Exon 6 of 6	2		ENSP00000387508.1
DARS1	ENST00000478212.5	n.380C>A		non_coding_transcript_exon_variant	Exon 3 of 3	2
DARS1	ENST00000489964.5	n.735C>A		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454528 Hom.: 0 Cov.: 30 AF XY: 0.00000415 AC XY: 3 AN XY: 723710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.73
MutPred		0.40		Gain of phosphorylation at P496 (P = 0.0083);.;
MVP		0.98
MPC		0.75
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.84
gMVP		0.91

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: rs1020492946; hg19: chr2-136664906;