NM_021830.5:c.1593-3T>C

Variant names:

• chr10-100990866-T-C
• rs3740486
• NM_021830.5:c.1593-3T>C

Variant summary

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

The NM_021830.5(TWNK):​c.1593-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,110 control chromosomes in the GnomAD database, including 51,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7428 hom., cov: 32)
  • Exomes 𝑓: 0.23 (44054 hom.)
• Consequence: TWNK NM_021830.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004419
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.152
• Publications: 21 publications found

Genes affected

TWNK (HGNC:1160): (twinkle mtDNA helicase) This gene encodes a hexameric DNA helicase which unwinds short stretches of double-stranded DNA in the 5' to 3' direction and, along with mitochondrial single-stranded DNA binding protein and mtDNA polymerase gamma, is thought to play a key role in mtDNA replication. The protein localizes to the mitochondrial matrix and mitochondrial nucleoids. Mutations in this gene cause infantile onset spinocerebellar ataxia (IOSCA) and progressive external ophthalmoplegia (PEO) and are also associated with several mitochondrial depletion syndromes. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Aug 2009]

TWNK Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial DNA depletion syndrome, hepatocerebrorenal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-100990866-T-C is Benign according to our data. Variant chr10-100990866-T-C is described in ClinVar as Benign. ClinVar VariationId is 136590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1593-3T>C		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000311916.8	NP_068602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWNK	ENST00000311916.8	c.1593-3T>C		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43675 AN: 151720 Hom.: 7403 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.274 AC: 68978 AN: 251474 AF XY: 0.266

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.550

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.231 AC: 337139 AN: 1460270 Hom.: 44054 Cov.: 33 AF XY: 0.231 AC XY: 167802 AN XY: 726500

African (AFR) AF: 0.470 AC: 15710 AN: 33434

American (AMR) AF: 0.365 AC: 16339 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3621 AN: 26130

East Asian (EAS) AF: 0.554 AC: 21973 AN: 39684

South Asian (SAS) AF: 0.292 AC: 25152 AN: 86224

European-Finnish (FIN) AF: 0.179 AC: 9566 AN: 53418

Middle Eastern (MID) AF: 0.210 AC: 1211 AN: 5764

European-Non Finnish (NFE) AF: 0.206 AC: 228672 AN: 1110568

Other (OTH) AF: 0.247 AC: 14895 AN: 60324

GnomAD4 genome AF: 0.288 AC: 43748 AN: 151840 Hom.: 7428 Cov.: 32 AF XY: 0.289 AC XY: 21484 AN XY: 74222

African (AFR) AF: 0.443 AC: 18292 AN: 41326

American (AMR) AF: 0.301 AC: 4592 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3470

East Asian (EAS) AF: 0.542 AC: 2784 AN: 5140

South Asian (SAS) AF: 0.304 AC: 1461 AN: 4808

European-Finnish (FIN) AF: 0.173 AC: 1831 AN: 10594

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13555 AN: 67954

Other (OTH) AF: 0.267 AC: 562 AN: 2106

Alfa AF: 0.236 Hom.: 2144

Bravo AF: 0.310

Asia WGS AF: 0.422 AC: 1466 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive cerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Infantile onset spinocerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.3
DANN	Benign	0.38
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.030		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: rs3740486; hg19: chr10-102750623; COSMIC: COSV54550548; COSMIC: COSV54550548;