NM_021830.5:c.1735-14C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021830.5(TWNK):c.1735-14C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,613,960 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 8 hom. )

Consequence

TWNK
NM_021830.5 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.272

Publications

1 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Orphanet
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

TWNK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 10-100993176-C-A is Benign according to our data. Variant chr10-100993176-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136594.

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TWNK	NM_021830.5	MANE Select	c.1735-14C>A	intron	N/A	NP_068602.2
TWNK	NM_001163812.2		c.*30-14C>A	intron	N/A	NP_001157284.1	Q96RR1-2
TWNK	NM_001163813.2		c.373-14C>A	intron	N/A	NP_001157285.1	A0A2R8Y4V4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TWNK	ENST00000311916.8	TSL:1 MANE Select	c.1735-14C>A	intron	N/A	ENSP00000309595.2	Q96RR1-1
TWNK	ENST00000370228.2	TSL:1	c.*30-14C>A	intron	N/A	ENSP00000359248.1	Q96RR1-2
TWNK	ENST00000473656.5	TSL:2	c.373-14C>A	intron	N/A	ENSP00000494326.1	A0A2R8Y4V4

Frequencies

GnomAD3 genomes

AF:

0.00126

AC:

192

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00220

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00104

AC:

262

AN:

251144

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00187

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00243

AC:

3547

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

1738

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33470

American (AMR)

AF:

0.000201

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000800

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.000730

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00293

AC:

3262

AN:

1111890

Other (OTH)

AF:

0.00252

AC:

152

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

177

354

532

709

886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00126

AC:

192

AN:

152296

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41560

American (AMR)

AF:

0.000458

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00220

AC:

150

AN:

68034

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000790

Hom.:

Bravo

AF:

0.00117

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Autosomal recessive cerebellar ataxia (1)

Infantile onset spinocerebellar ataxia (1)

not provided (1)

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (1)

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.6

(source)

DANN

Benign

0.68

PhyloP100

-0.27

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over