2-135957754-T-C

Variant names:

• chr2-135957754-T-C
• rs309142
• NM_001349.4:c.320+3642A>G

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+3642A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,032 control chromosomes in the GnomAD database, including 6,026 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 0.26 (6026 hom., cov: 31)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.19
• Publications: 10 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=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 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+3642A>G		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.20+3642A>G		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+3642A>G		intron	N/A	ENSP00000264161.4
	DARS1	ENST00000441323.5	TSL:3	c.221+3642A>G		intron	N/A	ENSP00000389867.1
	DARS1	ENST00000456565.5	TSL:3	c.221+3642A>G		intron	N/A	ENSP00000397616.1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39157 AN: 151914 Hom.: 5998 Cov.: 31

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.309

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.258 AC: 39238 AN: 152032 Hom.: 6026 Cov.: 31 AF XY: 0.261 AC XY: 19389 AN XY: 74328

African (AFR) AF: 0.378 AC: 15664 AN: 41426

American (AMR) AF: 0.267 AC: 4072 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1755 AN: 3472

East Asian (EAS) AF: 0.402 AC: 2079 AN: 5168

South Asian (SAS) AF: 0.309 AC: 1487 AN: 4820

European-Finnish (FIN) AF: 0.139 AC: 1473 AN: 10588

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.173 AC: 11779 AN: 67986

Other (OTH) AF: 0.313 AC: 660 AN: 2110

Alfa AF: 0.152 Hom.: 429

Bravo AF: 0.272

Asia WGS AF: 0.328 AC: 1140 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-1.2
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: rs309142; hg19: chr2-136715324;