rs17113613

Variant names:

• chr10-100989312-G-A
• rs17113613
• NM_021830.5:c.1102G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-100989312-G-A
• chr10-100989312-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_021830.5(TWNK):​c.1102G>A​(p.Val368Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,614,092 control chromosomes in the GnomAD database, including 866 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (346 hom., cov: 33)
  • Exomes 𝑓: 0.019 (520 hom.)
• Consequence: TWNK NM_021830.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.57
• Publications: 22 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 -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_021830.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.6071 (below the threshold of 3.09). Trascript score misZ: 2.58 (below the threshold of 3.09). GenCC associations: The gene is linked to progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, mitochondrial DNA depletion syndrome 7 (hepatocerebral type), Perrault syndrome, autosomal dominant progressive external ophthalmoplegia, mitochondrial DNA depletion syndrome, hepatocerebrorenal form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.00212875).
• BP6: Variant 10-100989312-G-A is Benign according to our data. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-100989312-G-A is described in CliVar as Benign. Clinvar id is 136588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1102G>A	p.Val368Ile	missense_variant	Exon 1 of 5	ENST00000311916.8	NP_068602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWNK	ENST00000311916.8	c.1102G>A	p.Val368Ile	missense_variant	Exon 1 of 5	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes AF: 0.0462 AC: 7027 AN: 152126 Hom.: 341 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0220 AC: 5521 AN: 251324 AF XY: 0.0190

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.00387

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0187 AC: 27363 AN: 1461848 Hom.: 520 Cov.: 32 AF XY: 0.0177 AC XY: 12875 AN XY: 727222

African (AFR) AF: 0.126 AC: 4234 AN: 33480

American (AMR) AF: 0.0234 AC: 1047 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00440 AC: 115 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00392 AC: 338 AN: 86258

European-Finnish (FIN) AF: 0.0301 AC: 1605 AN: 53376

Middle Eastern (MID) AF: 0.0212 AC: 122 AN: 5768

European-Non Finnish (NFE) AF: 0.0166 AC: 18466 AN: 1112012

Other (OTH) AF: 0.0238 AC: 1436 AN: 60394

GnomAD4 genome AF: 0.0463 AC: 7047 AN: 152244 Hom.: 346 Cov.: 33 AF XY: 0.0458 AC XY: 3411 AN XY: 74466

African (AFR) AF: 0.123 AC: 5118 AN: 41522

American (AMR) AF: 0.0323 AC: 494 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00807 AC: 28 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.0299 AC: 317 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 974 AN: 68018

Other (OTH) AF: 0.0469 AC: 99 AN: 2110

Alfa AF: 0.0221 Hom.: 338

Bravo AF: 0.0505

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.124 AC: 546

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.0227 AC: 2762

Asia WGS AF: 0.00924 AC: 33 AN: 3478

EpiCase AF: 0.0146

EpiControl AF: 0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 09, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 06, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:3

Jan 03, 2012

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. -

Dec 05, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive cerebellar ataxia Benign:1

Mar 06, 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

Mar 06, 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. -

Hereditary spastic paraplegia Benign:1

Dec 21, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Mar 06, 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

Mar 06, 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
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.084	T;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.85	D;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.92	L;L
PhyloP100		2.6
PROVEAN	Benign	-0.26	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.58	T;T
Sift4G	Benign	0.73	T;T
Polyphen		0.53	P;B
Vest4		0.051
MPC		0.44
ClinPred		0.010	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.046
gMVP		0.46
Mutation Taster		=99/1	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: rs17113613; hg19: chr10-102749069; COSMIC: COSV52966478; COSMIC: COSV52966478;