2-135927658-C-T

Variant names:

• chr2-135927658-C-T
• rs309160
• NM_001349.4:c.565-3160G>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.565-3160G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,832 control chromosomes in the GnomAD database, including 24,441 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 0.51 (24441 hom., cov: 32)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161
• Publications: 18 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

LOC124906078 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.814 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	NM_001349.4	MANE Select	c.565-3160G>A		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.265-3160G>A		intron	N/A	NP_001280241.1	P14868-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	ENST00000264161.9	TSL:1 MANE Select	c.565-3160G>A		intron	N/A	ENSP00000264161.4	P14868-1
	DARS1	ENST00000952144.1		c.565-3160G>A		intron	N/A	ENSP00000622203.1
	DARS1	ENST00000952145.1		c.565-3160G>A		intron	N/A	ENSP00000622204.1

Frequencies

GnomAD3 genomes AF: 0.511 AC: 77569 AN: 151714 Hom.: 24382 Cov.: 32

Gnomad AFR AF: 0.821

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.643

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.774

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.573

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.512 AC: 77685 AN: 151832 Hom.: 24441 Cov.: 32 AF XY: 0.520 AC XY: 38601 AN XY: 74180

African (AFR) AF: 0.821 AC: 34054 AN: 41476

American (AMR) AF: 0.609 AC: 9301 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2564 AN: 3468

East Asian (EAS) AF: 0.644 AC: 3322 AN: 5160

South Asian (SAS) AF: 0.653 AC: 3147 AN: 4816

European-Finnish (FIN) AF: 0.306 AC: 3204 AN: 10472

Middle Eastern (MID) AF: 0.781 AC: 228 AN: 292

European-Non Finnish (NFE) AF: 0.301 AC: 20447 AN: 67878

Other (OTH) AF: 0.576 AC: 1212 AN: 2104

Alfa AF: 0.397 Hom.: 24189

Bravo AF: 0.546

Asia WGS AF: 0.633 AC: 2192 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.70
PhyloP100		-0.16
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: rs309160; hg19: chr2-136685228;