2-135953494-C-T

Variant names:

• chr2-135953494-C-T
• rs3112496
• NM_001349.4:c.320+7902G>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.320+7902G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 151,920 control chromosomes in the GnomAD database, including 5,586 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 0.25 (5586 hom., cov: 32)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 6 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.382 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.320+7902G>A		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.20+7902G>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.320+7902G>A		intron	N/A	ENSP00000264161.4
	DARS1	ENST00000441323.5	TSL:3	c.221+7902G>A		intron	N/A	ENSP00000389867.1
	DARS1	ENST00000456565.5	TSL:3	c.221+7902G>A		intron	N/A	ENSP00000397616.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37481 AN: 151802 Hom.: 5556 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.283

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.295

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

GnomAD4 genome AF: 0.247 AC: 37565 AN: 151920 Hom.: 5586 Cov.: 32 AF XY: 0.250 AC XY: 18594 AN XY: 74234

African (AFR) AF: 0.376 AC: 15569 AN: 41396

American (AMR) AF: 0.255 AC: 3892 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1475 AN: 3466

East Asian (EAS) AF: 0.397 AC: 2053 AN: 5174

South Asian (SAS) AF: 0.282 AC: 1358 AN: 4812

European-Finnish (FIN) AF: 0.138 AC: 1446 AN: 10508

Middle Eastern (MID) AF: 0.418 AC: 122 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10887 AN: 67974

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.151 Hom.: 426

Bravo AF: 0.261

Asia WGS AF: 0.314 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.4
DANN	Benign	0.34
PhyloP100		-0.028
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: rs3112496; hg19: chr2-136711064;