dbSNP rs17113613: TWNK:p.Val368Ile (chr10-100989312-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.57

Publications

22 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 links:

MRPL43 (HGNC:14517): (mitochondrial ribosomal protein L43) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. This gene and the gene for a semaphorin class 4 protein (SEMA4G) overlap at map location 10q24.31 and are transcribed in opposite directions. Sequence analysis identified multiple transcript variants encoding at least four different protein isoforms. [provided by RefSeq, Jul 2008]

MRPL43 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 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, 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 ClinVar as Benign. ClinVar VariationId 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.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
TWNK	NM_021830.5	MANE Select	c.1102G>A	p.Val368Ile	missense	Exon 1 of 5	NP_068602.2
TWNK	NM_001163812.2		c.1102G>A	p.Val368Ile	missense	Exon 1 of 5	NP_001157284.1	Q96RR1-2
TWNK	NM_001163813.2		c.-119-332G>A		intron	N/A	NP_001157285.1	A0A2R8Y4V4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TWNK	ENST00000311916.8	TSL:1 MANE Select	c.1102G>A	p.Val368Ile	missense	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
TWNK	ENST00000370228.2	TSL:1	c.1102G>A	p.Val368Ile	missense	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
MRPL43	ENST00000858454.1		c.-236C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000528513.1

Frequencies

GnomAD3 genomes

AF:

0.0462

AC:

7027

AN:

152126

Hom.:

341

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0177

AC XY:

12875

AN XY:

727222

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

1860

3720

5579

7439

9299

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.0463

AC:

7047

AN:

152244

Hom.:

346

Cov.:

AF XY:

0.0458

AC XY:

3411

AN XY:

74466

show subpopulations

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:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0299

AC:

317

AN:

10612

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0143

AC:

974

AN:

68018

Other (OTH)

AF:

0.0469

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

318

636

954

1272

1590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0221

Hom.:

338

Bravo

AF:

0.0505

TwinsUK

AF:

0.0129

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.124

AC:

546

ESP6500EA

AF:

0.0176

AC:

151

ExAC

AF:

0.0227

AC:

2762

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0159

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Autosomal recessive cerebellar ataxia (1)

Hereditary spastic paraplegia (1)

Infantile onset spinocerebellar ataxia (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

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.084

Eigen

Benign

0.028

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.92

PhyloP100

2.6

PROVEAN

Benign

-0.26

REVEL

Uncertain

0.35

Sift

Benign

0.58

Sift4G

Benign

0.73

Polyphen

0.53

Vest4

0.051

MPC

0.44

ClinPred

0.010

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)

(source)

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

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