ENST00000441323.5:c.-50A>G

Variant names:

• chr2-135985829-T-C
• rs79018926
• ENST00000441323.5:c.-50A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000441323.5(DARS1):​c.-50A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 385,404 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0076 (11 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DARS1 ENST00000441323.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.58
• Publications: 1 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-AS1 (HGNC:40170): (DARS1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 2-135985829-T-C is Benign according to our data. Variant chr2-135985829-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1329551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00756 (1151/152326) while in subpopulation AFR AF = 0.0261 (1085/41574). AF 95% confidence interval is 0.0248. There are 11 homozygotes in GnomAd4. There are 575 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000441323.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1-AS1	NR_110199.1		n.341+313T>C		intron	N/A
	DARS1-AS1	NR_110200.1		n.341+313T>C		intron	N/A
	DARS1	NM_001349.4	MANE Select	c.-361A>G		upstream_gene	N/A	NP_001340.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	ENST00000441323.5	TSL:3	c.-50A>G		5_prime_UTR	Exon 1 of 8	ENSP00000389867.1	C9JLC1
	DARS1	ENST00000449218.5	TSL:3	c.-69A>G		5_prime_UTR	Exon 1 of 6	ENSP00000388801.1	C9JQM9
	DARS1	ENST00000456565.5	TSL:3	c.-34+101A>G		intron	N/A	ENSP00000397616.1	C9J7S3

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1144 AN: 152208 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00115 AC: 268 AN: 233078 Hom.: 2 Cov.: 3 AF XY: 0.00110 AC XY: 134 AN XY: 121906

African (AFR) AF: 0.0268 AC: 213 AN: 7960

American (AMR) AF: 0.00143 AC: 16 AN: 11162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7462

East Asian (EAS) AF: 0.00 AC: 0 AN: 15338

South Asian (SAS) AF: 0.000183 AC: 5 AN: 27252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1062

European-Non Finnish (NFE) AF: 0.0000291 AC: 4 AN: 137504

Other (OTH) AF: 0.00220 AC: 30 AN: 13654

GnomAD4 genome AF: 0.00756 AC: 1151 AN: 152326 Hom.: 11 Cov.: 33 AF XY: 0.00772 AC XY: 575 AN XY: 74502

African (AFR) AF: 0.0261 AC: 1085 AN: 41574

American (AMR) AF: 0.00346 AC: 53 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00612 Hom.: 1

Bravo AF: 0.00842

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.056
DANN	Benign	0.56
PhyloP100		-3.6
PromoterAI		0.0030	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs79018926; hg19: chr2-136743399;