rs309167

Variant names:

• chr2-135911694-C-T
• rs309167
• NM_001349.4:c.1231-201G>A

Variant summary

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

The NM_001349.4(DARS1):​c.1231-201G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 446,084 control chromosomes in the GnomAD database, including 8,716 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 0.18 (2821 hom., cov: 32)
  • Exomes 𝑓: 0.18 (5895 hom.)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.251
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349.4. 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	NM_001349.4	MANE Select	c.1231-201G>A		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.931-201G>A		intron	N/A	NP_001280241.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	ENST00000264161.9	TSL:1 MANE Select	c.1231-201G>A		intron	N/A	ENSP00000264161.4
	DARS1	ENST00000422708.3	TSL:2	c.292-201G>A		intron	N/A	ENSP00000387508.1
	DARS1	ENST00000489964.5	TSL:2	n.480-201G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27964 AN: 151956 Hom.: 2818 Cov.: 32

Gnomad AFR AF: 0.198

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.229

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.242

Gnomad FIN AF: 0.135

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.181 AC: 53106 AN: 294012 Hom.: 5895 AF XY: 0.186 AC XY: 28735 AN XY: 154588

African (AFR) AF: 0.202 AC: 1459 AN: 7232

American (AMR) AF: 0.201 AC: 1891 AN: 9390

Ashkenazi Jewish (ASJ) AF: 0.394 AC: 3756 AN: 9536

East Asian (EAS) AF: 0.145 AC: 3044 AN: 20962

South Asian (SAS) AF: 0.248 AC: 5448 AN: 21986

European-Finnish (FIN) AF: 0.139 AC: 2754 AN: 19762

Middle Eastern (MID) AF: 0.405 AC: 564 AN: 1392

European-Non Finnish (NFE) AF: 0.165 AC: 30586 AN: 185680

Other (OTH) AF: 0.199 AC: 3604 AN: 18072

GnomAD4 genome AF: 0.184 AC: 27985 AN: 152072 Hom.: 2821 Cov.: 32 AF XY: 0.187 AC XY: 13896 AN XY: 74332

African (AFR) AF: 0.197 AC: 8188 AN: 41482

American (AMR) AF: 0.229 AC: 3493 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 1334 AN: 3464

East Asian (EAS) AF: 0.191 AC: 992 AN: 5182

South Asian (SAS) AF: 0.242 AC: 1168 AN: 4822

European-Finnish (FIN) AF: 0.135 AC: 1427 AN: 10566

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.156 AC: 10616 AN: 67974

Other (OTH) AF: 0.248 AC: 522 AN: 2108

Alfa AF: 0.182 Hom.: 424

Bravo AF: 0.189

Asia WGS AF: 0.200 AC: 698 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.54
PhyloP100		-0.25
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: rs309167; hg19: chr2-136669264;