2-135907405-A-G

Position:

• chr2-135907405-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001349.4(DARS1):​c.1417T>C​(p.Leu473=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00798 in 1,608,994 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (90 hom., cov: 31)
  • Exomes 𝑓: 0.0064 (180 hom.)
• Consequence: DARS1 NM_001349.4 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-135907405-A-G is Benign according to our data. Variant chr2-135907405-A-G is described in ClinVar as [Benign]. Clinvar id is 380521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.6 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DARS1	NM_001349.4	c.1417T>C	p.Leu473=	splice_region_variant, synonymous_variant	16/16	ENST00000264161.9
DARS1	NM_001293312.1	c.1117T>C	p.Leu373=	splice_region_variant, synonymous_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DARS1	ENST00000264161.9	c.1417T>C	p.Leu473=	splice_region_variant, synonymous_variant	16/16	1	NM_001349.4	P1
DARS1	ENST00000422708.3	c.478T>C	p.Leu160=	splice_region_variant, synonymous_variant	6/6	2
DARS1	ENST00000478212.5	n.311T>C		splice_region_variant, non_coding_transcript_exon_variant	3/3	2
DARS1	ENST00000489964.5	n.666T>C		splice_region_variant, non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3408 AN: 152064 Hom.: 83 Cov.: 31

Gnomad AFR AF: 0.0654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.00865

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0120 AC: 2960 AN: 246774 Hom.: 51 AF XY: 0.0120 AC XY: 1606 AN XY: 133692

Gnomad AFR exome AF: 0.0660

Gnomad AMR exome AF: 0.00444

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00561

Gnomad SAS exome AF: 0.0298

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.0119

GnomAD4 exome AF: 0.00644 AC: 9388 AN: 1456812 Hom.: 180 Cov.: 29 AF XY: 0.00701 AC XY: 5083 AN XY: 725006

Gnomad4 AFR exome AF: 0.0678

Gnomad4 AMR exome AF: 0.00516

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.00148

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0227 AC: 3451 AN: 152182 Hom.: 90 Cov.: 31 AF XY: 0.0231 AC XY: 1718 AN XY: 74406

Gnomad4 AFR AF: 0.0662

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0122 Hom.: 10

Bravo AF: 0.0247

Asia WGS AF: 0.0330 AC: 115 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00464

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.6
DANN	Benign	0.48

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;