rs367543010

Variant names:

• chr1-173828312-T-TC
• rs367543010
• NM_018122.5:c.228-21_228-20insC

Your query was ambiguous. Multiple possible variants found:

• chr1-173828312-T-TC
• chr1-173828312-T-TCC
• chr1-173828312-T-TCGG
• chr1-173828312-T-TGGG
• chr1-173828312-T-TGGGG
• chr1-173828312-T-TGGGGG
• chr1-173828312-T-TGGGGGG
• chr1-173828312-T-TGGGGGGGGGGGG
• chr1-173828312-T-TGGGGGGGGGGGGG
• chr1-173828312-T-TGGGGGGGGGGGGGGG
• chr1-173828312-T-TGGGGGGGGGGGGGGGG
• chr1-173828312-T-TGGGGGGGGGGGGGGGGGGGGGGGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_018122.5(DARS2):​c.228-21_228-20insC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00361 in 1,547,144 control chromosomes in the GnomAD database, including 52 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (24 hom., cov: 27)
  • Exomes 𝑓: 0.0033 (28 hom.)
• Consequence: DARS2 NM_018122.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.51
• Publications: 1 publications found

Genes affected

DARS2 (HGNC:25538): (aspartyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. It is a mitochondrial enzyme that specifically aminoacylates aspartyl-tRNA. Mutations in this gene are associated with leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). [provided by RefSeq, Nov 2009]

DARS2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-173828312-T-TC is Benign according to our data. Variant chr1-173828312-T-TC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 559195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018122.5. 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
	DARS2	NM_018122.5	MANE Select	c.228-21_228-20insC		intron	N/A	NP_060592.2
	DARS2	NM_001365212.1		c.228-21_228-20insC		intron	N/A	NP_001352141.1	A0A3B3IT01
	DARS2	NM_001365213.2		c.228-21_228-20insC		intron	N/A	NP_001352142.1	A0A3B3ITS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DARS2	ENST00000649689.2	MANE Select	c.228-21_228-20insC		intron	N/A	ENSP00000497569.1	Q6PI48
	DARS2	ENST00000647645.1		c.228-21_228-20insC		intron	N/A	ENSP00000497450.1	A0A3B3ISK7
	DARS2	ENST00000893356.1		c.228-21_228-20insC		intron	N/A	ENSP00000563415.1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 992 AN: 149298 Hom.: 24 Cov.: 27

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.0108

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.000905

Gnomad OTH AF: 0.00341

GnomAD2 exomes AF: 0.00591 AC: 1431 AN: 242088 AF XY: 0.00708

Gnomad AFR exome AF: 0.00607

Gnomad AMR exome AF: 0.00207

Gnomad ASJ exome AF: 0.00385

Gnomad EAS exome AF: 0.00967

Gnomad FIN exome AF: 0.000513

Gnomad NFE exome AF: 0.000939

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00329 AC: 4593 AN: 1397728 Hom.: 28 Cov.: 22 AF XY: 0.00422 AC XY: 2939 AN XY: 695708

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00500 AC: 161 AN: 32178

American (AMR) AF: 0.00181 AC: 79 AN: 43734

Ashkenazi Jewish (ASJ) AF: 0.00454 AC: 111 AN: 24462

East Asian (EAS) AF: 0.00737 AC: 279 AN: 37864

South Asian (SAS) AF: 0.0331 AC: 2660 AN: 80434

European-Finnish (FIN) AF: 0.00111 AC: 58 AN: 52020

Middle Eastern (MID) AF: 0.00488 AC: 27 AN: 5528

European-Non Finnish (NFE) AF: 0.000970 AC: 1032 AN: 1063992

Other (OTH) AF: 0.00323 AC: 186 AN: 57516

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00667 AC: 996 AN: 149416 Hom.: 24 Cov.: 27 AF XY: 0.00787 AC XY: 574 AN XY: 72968

African (AFR) AF: 0.0119 AC: 481 AN: 40388

American (AMR) AF: 0.00221 AC: 33 AN: 14900

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 37 AN: 3440

East Asian (EAS) AF: 0.0167 AC: 85 AN: 5084

South Asian (SAS) AF: 0.0625 AC: 290 AN: 4642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10262

Middle Eastern (MID) AF: 0.00690 AC: 2 AN: 290

European-Non Finnish (NFE) AF: 0.000905 AC: 61 AN: 67432

Other (OTH) AF: 0.00338 AC: 7 AN: 2070

Alfa AF: 0.00359 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=100/0	polymorphism

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: rs367543010; hg19: chr1-173797450;