chr2-135951217-G-C

Variant names:

• chr2-135951217-G-C
• rs309120
• NM_001349.4:c.321-7737C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000264161.9(DARS1):​c.321-7737C>G 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 152,092 control chromosomes in the GnomAD database, including 5,581 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 (5581 hom., cov: 32)
• Consequence: DARS1 ENST00000264161.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.124
• Publications: 2 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=-1.0).
• 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: ENST00000264161.9. 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.321-7737C>G		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.21-7737C>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.321-7737C>G		intron	N/A	ENSP00000264161.4
	DARS1	ENST00000441323.5	TSL:3	c.222-7737C>G		intron	N/A	ENSP00000389867.1
	DARS1	ENST00000456565.5	TSL:3	c.222-7737C>G		intron	N/A	ENSP00000397616.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37492 AN: 151976 Hom.: 5550 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: 0.396

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.247 AC: 37576 AN: 152092 Hom.: 5581 Cov.: 32 AF XY: 0.250 AC XY: 18607 AN XY: 74364

African (AFR) AF: 0.376 AC: 15564 AN: 41448

American (AMR) AF: 0.255 AC: 3893 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1476 AN: 3466

East Asian (EAS) AF: 0.397 AC: 2052 AN: 5174

South Asian (SAS) AF: 0.282 AC: 1358 AN: 4816

European-Finnish (FIN) AF: 0.137 AC: 1451 AN: 10590

Middle Eastern (MID) AF: 0.415 AC: 122 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10897 AN: 68008

Other (OTH) AF: 0.300 AC: 633 AN: 2108

Alfa AF: 0.215 Hom.: 531

Bravo AF: 0.261

Asia WGS AF: 0.313 AC: 1089 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	0.73
DANN	Benign	0.27
PhyloP100		-0.12
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: rs309120; hg19: chr2-136708787;