rs1554887213

Variant names:

• chr10-100989774-G-T
• rs1554887213
• NM_021830.5:c.1374G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Moderate

The NM_021830.5(TWNK):​c.1374G>T​(p.Gln458His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TWNK NM_021830.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.54
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_021830.5
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 10-100989774-G-T is Pathogenic according to our data. Variant chr10-100989774-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 426104.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1374G>T	p.Gln458His	missense_variant	Exon 2 of 5	ENST00000311916.8	NP_068602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWNK	ENST00000311916.8	c.1374G>T	p.Gln458His	missense_variant	Exon 2 of 5	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286), mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MIM#271245) and Perrault syndrome 5 (MIM#616138) (PMID: 18971204). (I) 0108 - This gene is associated with both recessive and dominant disease. Mitochondrial DNA depletion syndrome 7 (hepatocerebral type) (MIM#271245) and Perrault syndrome 5 (MIM#616138) are inherited in a recessive manner, whereas progressive external ophthalmoplegia with mitochondrial DNA deletions 3 (MIM#609286) is a dominant condition (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to histidine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located between two Walker a/b motifs and within the helicase functional domain (PMID: 20479361). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in at least four heterozygous individuals with mitochondrial disease or progressive external ophthalmoplegia with ptosis (ClinVar, PMID: 28812649, PMID: 34732400, PMID: 20479361, PMID: 26469001). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Testing of this individual’s mother has shown that the variant was not maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	.;D;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.2	.;M;M;.;.
PhyloP100		3.5
PROVEAN	Pathogenic	-4.8	.;D;D;.;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	.;D;D;.;.
Sift4G	Pathogenic	0.0	.;D;D;.;.
Polyphen		1.0, 1.0	.;D;D;.;.
Vest4		0.90, 0.92
MutPred		0.81		.;Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		2.2
Varity_R		0.84
gMVP		0.97
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554887213; hg19: chr10-102749531;