rs886037832
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_021830.5(TWNK):c.333delT(p.Leu112SerfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TWNK
NM_021830.5 frameshift
NM_021830.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.79
Publications
1 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 3Inheritance: 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 ophthalmoplegiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial DNA depletion syndrome, hepatocerebrorenal formInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- Perrault syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 11 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-100988540-CT-C is Pathogenic according to our data. Variant chr10-100988540-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 225837.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_021830.5. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TWNK | NM_021830.5 | MANE Select | c.333delT | p.Leu112SerfsTer3 | frameshift | Exon 1 of 5 | NP_068602.2 | ||
| TWNK | NM_001163812.2 | c.333delT | p.Leu112SerfsTer3 | frameshift | Exon 1 of 5 | NP_001157284.1 | |||
| TWNK | NR_160738.1 | n.1001delT | non_coding_transcript_exon | Exon 1 of 5 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TWNK | ENST00000311916.8 | TSL:1 MANE Select | c.333delT | p.Leu112SerfsTer3 | frameshift | Exon 1 of 5 | ENSP00000309595.2 | ||
| TWNK | ENST00000370228.2 | TSL:1 | c.333delT | p.Leu112SerfsTer3 | frameshift | Exon 1 of 5 | ENSP00000359248.1 | ||
| TWNK | ENST00000643860.1 | n.333delT | non_coding_transcript_exon | Exon 1 of 5 | ENSP00000494389.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727210 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461824
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727210
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53354
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1112010
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions as Germline
Significance:Pathogenic
Revision:no assertion criteria provided
Pathogenic
VUS
Benign
Condition
1
-
-
Infantile onset spinocerebellar ataxia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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