chr2-135961603-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 16 publications found

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]

DARS1 Gene-Disease associations (from GenCC):

• hypomyelination with brain stem and spinal cord involvement and leg spasticity

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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

African (AFR) AF: 0.121 AC: 1887 AN: 15606

American (AMR) AF: 0.196 AC: 6218 AN: 31720

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 8199 AN: 17740

East Asian (EAS) AF: 0.161 AC: 5071 AN: 31540

South Asian (SAS) AF: 0.268 AC: 15854 AN: 59208

European-Finnish (FIN) AF: 0.144 AC: 6366 AN: 44222

Middle Eastern (MID) AF: 0.356 AC: 1387 AN: 3900

European-Non Finnish (NFE) AF: 0.172 AC: 57322 AN: 333298

Other (OTH) AF: 0.212 AC: 6368 AN: 30070

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

African (AFR) AF: 0.122 AC: 5052 AN: 41472

American (AMR) AF: 0.231 AC: 3532 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 1601 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1016 AN: 5168

South Asian (SAS) AF: 0.262 AC: 1262 AN: 4816

European-Finnish (FIN) AF: 0.137 AC: 1448 AN: 10564

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.169 AC: 11494 AN: 67988

Other (OTH) AF: 0.247 AC: 522 AN: 2114

Alfa AF: 0.183 Hom.: 650

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.28
PhyloP100		-0.012
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6430594; hg19: chr2-136719173; COSMIC: COSV107253654;