NM_001349.4:c.-105C>G

Variant names:

• chr2-135985573-G-C
• rs2278682
• NM_001349.4:c.-105C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001349.4(DARS1):​c.-105C>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 0.167 in 1,584,088 control chromosomes in the GnomAD database, including 28,836 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4406 hom., cov: 32)
  • Exomes 𝑓: 0.16 (24430 hom.)
• Consequence: DARS1 NM_001349.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.22
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-135985573-G-C is Benign according to our data. Variant chr2-135985573-G-C is described in ClinVar as Benign. ClinVar VariationId is 1181810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.381 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.-105C>G		5_prime_UTR	Exon 1 of 16	NP_001340.2
	DARS1	NM_001293312.1		c.-347C>G		5_prime_UTR	Exon 1 of 15	NP_001280241.1	P14868-2
	DARS1-AS1	NR_110199.1		n.341+57G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS1	ENST00000264161.9	TSL:1 MANE Select	c.-105C>G		5_prime_UTR	Exon 1 of 16	ENSP00000264161.4	P14868-1
	DARS1	ENST00000952144.1		c.-105C>G		5_prime_UTR	Exon 1 of 16	ENSP00000622203.1
	DARS1	ENST00000952145.1		c.-105C>G		5_prime_UTR	Exon 1 of 16	ENSP00000622204.1

Frequencies

GnomAD3 genomes AF: 0.223 AC: 33907 AN: 152006 Hom.: 4384 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.274

GnomAD2 exomes AF: 0.226 AC: 44724 AN: 197716 AF XY: 0.230

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.448

Gnomad EAS exome AF: 0.414

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.161 AC: 230880 AN: 1431964 Hom.: 24430 Cov.: 31 AF XY: 0.167 AC XY: 118622 AN XY: 709284

African (AFR) AF: 0.314 AC: 10398 AN: 33066

American (AMR) AF: 0.198 AC: 7730 AN: 39048

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 11228 AN: 25344

East Asian (EAS) AF: 0.352 AC: 13584 AN: 38594

South Asian (SAS) AF: 0.283 AC: 23428 AN: 82804

European-Finnish (FIN) AF: 0.143 AC: 7298 AN: 51114

Middle Eastern (MID) AF: 0.370 AC: 2115 AN: 5710

European-Non Finnish (NFE) AF: 0.130 AC: 142901 AN: 1097000

Other (OTH) AF: 0.206 AC: 12198 AN: 59284

GnomAD4 genome AF: 0.223 AC: 33978 AN: 152124 Hom.: 4406 Cov.: 32 AF XY: 0.228 AC XY: 16941 AN XY: 74398

African (AFR) AF: 0.293 AC: 12176 AN: 41528

American (AMR) AF: 0.246 AC: 3770 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1478 AN: 3470

East Asian (EAS) AF: 0.396 AC: 2039 AN: 5154

South Asian (SAS) AF: 0.282 AC: 1357 AN: 4814

European-Finnish (FIN) AF: 0.137 AC: 1455 AN: 10606

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10863 AN: 67932

Other (OTH) AF: 0.280 AC: 591 AN: 2114

Alfa AF: 0.231 Hom.: 942

Bravo AF: 0.234

Asia WGS AF: 0.306 AC: 1066 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.9
DANN	Benign	0.86
PhyloP100		-1.2
PromoterAI		0.081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2278682; hg19: chr2-136743143; COSMIC: COSV51536943; COSMIC: COSV51536943;