chr2-135961603-A-G

Variant names:

• chr2-135961603-A-G
• rs6430594
• NM_001349.4:c.218-105T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349.4(DARS1):​c.218-105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 719,360 control chromosomes in the GnomAD database, including 15,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2652 hom., cov: 32)
  • Exomes 𝑓: 0.19 (12953 hom.)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0120

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-135961603-A-G is Benign according to our data. Variant chr2-135961603-A-G is described in ClinVar as [Benign]. Clinvar id is 1241946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.218-105T>C		intron_variant	Intron 3 of 15	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.-83-105T>C		intron_variant	Intron 2 of 14		NP_001280241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.218-105T>C		intron_variant	Intron 3 of 15	1	NM_001349.4	ENSP00000264161.4

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26180 AN: 151938 Hom.: 2654 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.461

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.243

GnomAD4 exome AF: 0.192 AC: 108672 AN: 567304 Hom.: 12953 AF XY: 0.200 AC XY: 60564 AN XY: 303322

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.268

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.212

GnomAD4 genome AF: 0.172 AC: 26188 AN: 152056 Hom.: 2652 Cov.: 32 AF XY: 0.175 AC XY: 13031 AN XY: 74334

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.231

Gnomad4 ASJ AF: 0.461

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.247

Alfa AF: 0.185 Hom.: 642

Bravo AF: 0.174

Asia WGS AF: 0.204 AC: 710 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.28

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: rs6430594; hg19: chr2-136719173;