2-135985510-G-C

Variant names:

• chr2-135985510-G-C
• rs11548872
• NM_001349.4:c.-42C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001349.4(DARS1):​c.-42C>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 0.00603 in 1,613,704 control chromosomes in the GnomAD database, including 737 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (99 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (638 hom.)
• Consequence: DARS1 NM_001349.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-135985510-G-C is Benign according to our data. Variant chr2-135985510-G-C is described in ClinVar as Benign. ClinVar VariationId is 381868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	NM_001349.4	MANE Select	c.-42C>G		5_prime_UTR	Exon 1 of 16	NP_001340.2
	DARS1	NM_001293312.1		c.-284C>G		5_prime_UTR	Exon 1 of 15	NP_001280241.1	P14868-2
	DARS1-AS1	NR_110199.1		n.335G>C		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	ENST00000264161.9	TSL:1 MANE Select	c.-42C>G		5_prime_UTR	Exon 1 of 16	ENSP00000264161.4	P14868-1
	DARS1	ENST00000952144.1		c.-42C>G		5_prime_UTR	Exon 1 of 16	ENSP00000622203.1
	DARS1	ENST00000952145.1		c.-42C>G		5_prime_UTR	Exon 1 of 16	ENSP00000622204.1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152162 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.0161 AC: 4016 AN: 249648 AF XY: 0.0149

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000928

Gnomad ASJ exome AF: 0.00777

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.000563

Gnomad NFE exome AF: 0.000372

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.00586 AC: 8558 AN: 1461424 Hom.: 638 Cov.: 31 AF XY: 0.00584 AC XY: 4243 AN XY: 727030

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.000783 AC: 35 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00846 AC: 221 AN: 26110

East Asian (EAS) AF: 0.172 AC: 6834 AN: 39684

South Asian (SAS) AF: 0.00640 AC: 552 AN: 86210

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53352

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000212 AC: 236 AN: 1111752

Other (OTH) AF: 0.0106 AC: 643 AN: 60380

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152280 Hom.: 99 Cov.: 32 AF XY: 0.00878 AC XY: 654 AN XY: 74468

African (AFR) AF: 0.000192 AC: 8 AN: 41578

American (AMR) AF: 0.000915 AC: 14 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3472

East Asian (EAS) AF: 0.195 AC: 1009 AN: 5170

South Asian (SAS) AF: 0.0112 AC: 54 AN: 4822

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68004

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00947

Asia WGS AF: 0.0720 AC: 251 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Uncertain	0.99
PhyloP100		2.2
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=298/2	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: rs11548872; hg19: chr2-136743080; COSMIC: COSV51537930; COSMIC: COSV51537930;