2-135962774-G-T

Variant names:

• chr2-135962774-G-T
• rs3768998
• NM_001349.4:c.218-1276C>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.218-1276C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,078 control chromosomes in the GnomAD database, including 4,060 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 0.20 (4060 hom., cov: 32)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• Publications: 4 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.218-1276C>A		intron_variant	Intron 3 of 15	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.-83-1276C>A		intron_variant	Intron 2 of 14		NP_001280241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.218-1276C>A		intron_variant	Intron 3 of 15	1	NM_001349.4	ENSP00000264161.4

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30663 AN: 151960 Hom.: 4050 Cov.: 32

Gnomad AFR AF: 0.326

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.225

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

GnomAD4 genome AF: 0.202 AC: 30703 AN: 152078 Hom.: 4060 Cov.: 32 AF XY: 0.208 AC XY: 15454 AN XY: 74320

African (AFR) AF: 0.327 AC: 13548 AN: 41474

American (AMR) AF: 0.304 AC: 4653 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3468

East Asian (EAS) AF: 0.180 AC: 935 AN: 5184

South Asian (SAS) AF: 0.333 AC: 1606 AN: 4818

European-Finnish (FIN) AF: 0.143 AC: 1504 AN: 10544

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7176 AN: 67990

Other (OTH) AF: 0.223 AC: 472 AN: 2114

Alfa AF: 0.0770 Hom.: 113

Bravo AF: 0.219

Asia WGS AF: 0.283 AC: 984 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.3
DANN	Benign	0.38
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: rs3768998; hg19: chr2-136720344;