ENST00000444406.1:n.226A>C

Variant names:

• chr2-135985920-A-C
• rs2278683
• ENST00000444406.1:n.226A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000444406.1(DARS1-AS1):​n.226A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 176,312 control chromosomes in the GnomAD database, including 4,055 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 0.19 (3344 hom., cov: 32)
  • Exomes 𝑓: 0.21 (711 hom.)
• Consequence: DARS1-AS1 ENST00000444406.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00400
• Publications: 9 publications found

Genes affected

DARS1-AS1 (HGNC:40170): (DARS1 antisense RNA 1)

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000444406.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1-AS1	NR_110199.1		n.341+404A>C		intron	N/A
	DARS1-AS1	NR_110200.1		n.341+404A>C		intron	N/A
	DARS1	NM_001293312.1		c.-694T>G		upstream_gene	N/A	NP_001280241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1-AS1	ENST00000444406.1	TSL:2	n.226A>C		non_coding_transcript_exon	Exon 2 of 2
	DARS1-AS1	ENST00000764020.1		n.383A>C		non_coding_transcript_exon	Exon 2 of 6
	DARS1-AS1	ENST00000764027.1		n.136A>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28834 AN: 152064 Hom.: 3340 Cov.: 32

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.307

Gnomad ASJ AF: 0.273

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.354

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.218

GnomAD4 exome AF: 0.206 AC: 4960 AN: 24130 Hom.: 711 Cov.: 0 AF XY: 0.222 AC XY: 2970 AN XY: 13382

African (AFR) AF: 0.280 AC: 276 AN: 986

American (AMR) AF: 0.353 AC: 812 AN: 2300

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 149 AN: 520

East Asian (EAS) AF: 0.198 AC: 225 AN: 1136

South Asian (SAS) AF: 0.341 AC: 1564 AN: 4586

European-Finnish (FIN) AF: 0.160 AC: 102 AN: 636

Middle Eastern (MID) AF: 0.279 AC: 24 AN: 86

European-Non Finnish (NFE) AF: 0.126 AC: 1603 AN: 12694

Other (OTH) AF: 0.173 AC: 205 AN: 1186

GnomAD4 genome AF: 0.190 AC: 28854 AN: 152182 Hom.: 3344 Cov.: 32 AF XY: 0.197 AC XY: 14640 AN XY: 74408

African (AFR) AF: 0.248 AC: 10284 AN: 41492

American (AMR) AF: 0.306 AC: 4686 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 948 AN: 3472

East Asian (EAS) AF: 0.191 AC: 990 AN: 5178

South Asian (SAS) AF: 0.353 AC: 1706 AN: 4830

European-Finnish (FIN) AF: 0.145 AC: 1539 AN: 10592

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8072 AN: 68002

Other (OTH) AF: 0.217 AC: 459 AN: 2116

Alfa AF: 0.152 Hom.: 4802

Bravo AF: 0.203

Asia WGS AF: 0.286 AC: 994 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.56
PhyloP100		0.0040
PromoterAI		-0.013	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2278683; hg19: chr2-136743490;