NM_001349.4:c.320+4788T>C

Variant names:

• chr2-135956608-A-G
• rs309143
• NM_001349.4:c.320+4788T>C

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+4788T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.195 in 152,098 control chromosomes in the GnomAD database, including 3,224 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 (3224 hom., cov: 31)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.108
• Publications: 14 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.320+4788T>C		intron_variant	Intron 4 of 15	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.20+4788T>C		intron_variant	Intron 3 of 14		NP_001280241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.320+4788T>C		intron_variant	Intron 4 of 15	1	NM_001349.4	ENSP00000264161.4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29660 AN: 151980 Hom.: 3224 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.257

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

GnomAD4 genome AF: 0.195 AC: 29677 AN: 152098 Hom.: 3224 Cov.: 31 AF XY: 0.198 AC XY: 14690 AN XY: 74370

African (AFR) AF: 0.200 AC: 8314 AN: 41482

American (AMR) AF: 0.241 AC: 3686 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1613 AN: 3470

East Asian (EAS) AF: 0.198 AC: 1022 AN: 5174

South Asian (SAS) AF: 0.262 AC: 1263 AN: 4818

European-Finnish (FIN) AF: 0.138 AC: 1456 AN: 10584

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11507 AN: 67970

Other (OTH) AF: 0.261 AC: 552 AN: 2116

Alfa AF: 0.186 Hom.: 1979

Bravo AF: 0.201

Asia WGS AF: 0.209 AC: 728 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.9
DANN	Benign	0.70
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs309143; hg19: chr2-136714178;