rs551090724

Variant names:

• chr2-135985447-G-GGCTGGC
• rs551090724
• NM_001349.4:c.16_21dupGCCAGC

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS1

The NM_001349.4(DARS1):​c.16_21dupGCCAGC​(p.Ser7_Arg8insAlaSer) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,613,926 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (1 hom.)
• Consequence: DARS1 NM_001349.4 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.18

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001349.4.
• BP6: Variant 2-135985447-G-GGCTGGC is Benign according to our data. Variant chr2-135985447-G-GGCTGGC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 808803.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000289 (44/152334) while in subpopulation SAS AF= 0.00394 (19/4826). AF 95% confidence interval is 0.00258. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DARS1	NM_001349.4	c.16_21dupGCCAGC	p.Ser7_Arg8insAlaSer	conservative_inframe_insertion	Exon 1 of 16	ENST00000264161.9	NP_001340.2
DARS1	NM_001293312.1	c.-227_-222dupGCCAGC		5_prime_UTR_variant	Exon 1 of 15		NP_001280241.1
DARS1-AS1	NR_110199.1	n.284_289dupCGCTGG		non_coding_transcript_exon_variant	Exon 1 of 4
DARS1-AS1	NR_110200.1	n.284_289dupCGCTGG		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DARS1	ENST00000264161.9	c.16_21dupGCCAGC	p.Ser7_Arg8insAlaSer	conservative_inframe_insertion	Exon 1 of 16	1	NM_001349.4	ENSP00000264161.4

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152216 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000520 AC: 130 AN: 250022 Hom.: 1 AF XY: 0.000679 AC XY: 92 AN XY: 135398

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461592 Hom.: 1 Cov.: 31 AF XY: 0.000430 AC XY: 313 AN XY: 727132

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00381

Gnomad4 FIN exome AF: 0.0000751

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152334 Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74482

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000159

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs551090724; hg19: chr2-136743017;