2-135924704-A-T

Variant names:

• chr2-135924704-A-T
• rs192822
• NM_001349.4:c.565-206T>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.565-206T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 152,032 control chromosomes in the GnomAD database, including 19,288 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 0.47 (19288 hom., cov: 32)
• Consequence: DARS1 NM_001349.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0660
• Publications: 7 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 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.565-206T>A		intron	N/A	NP_001340.2
	DARS1	NM_001293312.1		c.265-206T>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.565-206T>A		intron	N/A	ENSP00000264161.4
	DARS1	ENST00000441323.5	TSL:3	c.466-206T>A		intron	N/A	ENSP00000389867.1
	DARS1	ENST00000456565.5	TSL:3	c.466-206T>A		intron	N/A	ENSP00000397616.1

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70656 AN: 151914 Hom.: 19233 Cov.: 32

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.591

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.646

Gnomad SAS AF: 0.654

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.772

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.543

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

GnomAD4 genome AF: 0.466 AC: 70771 AN: 152032 Hom.: 19288 Cov.: 32 AF XY: 0.476 AC XY: 35352 AN XY: 74316

African (AFR) AF: 0.662 AC: 27447 AN: 41460

American (AMR) AF: 0.591 AC: 9029 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2566 AN: 3470

East Asian (EAS) AF: 0.647 AC: 3350 AN: 5176

South Asian (SAS) AF: 0.652 AC: 3142 AN: 4818

European-Finnish (FIN) AF: 0.304 AC: 3210 AN: 10556

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20438 AN: 67962

Other (OTH) AF: 0.546 AC: 1152 AN: 2108

Alfa AF: 0.408 Hom.: 1764

Bravo AF: 0.494

Asia WGS AF: 0.628 AC: 2184 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.3
DANN	Benign	0.34
PhyloP100		0.066
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: rs192822; hg19: chr2-136682274;