rs28937887

Variant names:

• chr10-100989211-G-A
• rs28937887
• NM_021830.5:c.1001G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-100989211-G-A
• chr10-100989211-G-C
• chr10-100989211-G-T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_021830.5(TWNK):​c.1001G>A​(p.Arg334Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TWNK NM_021830.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.18
• Publications: 11 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_021830.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-100989211-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2735473.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.
• PP5: Variant 10-100989211-G-A is Pathogenic according to our data. Variant chr10-100989211-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1001G>A	p.Arg334Gln	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.1001G>A	p.Arg334Gln	missense_variant	Exon 1 of 5	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 334 of the TWNK protein (p.Arg334Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of autosomal dominant progressive external ophthalmoplegia with mitochondrial DNA deletions (PMID: 12707443, 18973250, 24086434; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4623). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt TWNK protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on TWNK function (PMID: 19084593, 20659899, 30496414). This variant disrupts the p.Arg334 amino acid residue in TWNK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18575922). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mitochondrial disease Pathogenic:1

Apr 07, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Dec 08, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, digenic Pathogenic:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Infantile onset spinocerebellar ataxia Pathogenic:1

-

Genomics England Pilot Project, Genomics England

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		4.2
PROVEAN	Uncertain	-2.7	D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.057	T;T
Sift4G	Benign	0.090	T;T
Polyphen		0.86	P;D
Vest4		0.66
MutPred		0.78		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		1.0
MPC		0.75
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.19
gMVP		0.78
Mutation Taster		=72/28	disease causing (ClinVar)

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: rs28937887; hg19: chr10-102748968;