2-135962774-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001349.4(DARS1):c.218-1276C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,078 control chromosomes in the GnomAD database, including 4,060 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (4060 hom., cov: 32)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS1	NM_001349.4	c.218-1276C>A		intron_variant		ENST00000264161.9
DARS1	NM_001293312.1	c.-83-1276C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS1	ENST00000264161.9	c.218-1276C>A		intron_variant		1	NM_001349.4	P1

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30663 AN: 151960 Hom.: 4050 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.225

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.202 AC: 30703 AN: 152078 Hom.: 4060 Cov.: 32 AF XY: 0.208 AC XY: 15454 AN XY: 74320

Gnomad4 AFR AF: 0.327

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.106

Gnomad4 OTH AF: 0.223

Alfa AF: 0.0648 Hom.: 68

Bravo AF: 0.219

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	2.3
Dann	Benign	0.38

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: rs3768998; hg19: chr2-136720344;