NM_021830.5:c.-290G>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_021830.5(TWNK):c.-290G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 613,756 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TWNK
NM_021830.5 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.178

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 10-100987921-G-C is Benign according to our data. Variant chr10-100987921-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 298491.

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.-290G>C	5_prime_UTR	Exon 1 of 5	NP_068602.2
TWNK	NM_001163812.2		c.-290G>C	5_prime_UTR	Exon 1 of 5	NP_001157284.1	Q96RR1-2
TWNK	NM_001163813.2		c.-120+308G>C	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.-290G>C	5_prime_UTR	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
TWNK	ENST00000370228.2	TSL:1	c.-290G>C	5_prime_UTR	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
TWNK	ENST00000473656.5	TSL:2	c.-120+308G>C	intron	N/A	ENSP00000494326.1	A0A2R8Y4V4

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.000119

AC:

AN:

461404

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

244728

show subpopulations

African (AFR)

AF:

0.0000786

AC:

AN:

12720

American (AMR)

AF:

0.000541

AC:

AN:

20344

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14022

East Asian (EAS)

AF:

0.00

AC:

AN:

31468

South Asian (SAS)

AF:

0.00

AC:

AN:

47408

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29850

Middle Eastern (MID)

AF:

0.000998

AC:

AN:

2004

European-Non Finnish (NFE)

AF:

0.000130

AC:

AN:

276996

Other (OTH)

AF:

0.000188

AC:

AN:

26592

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000138

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41582

American (AMR)

AF:

0.000784

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68040

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.00

Hom.:

Bravo

AF:

0.000196

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive cerebellar ataxia (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

BayesDel_noAF

Benign

-0.96

CADD

Benign

7.4

(source)

DANN

Benign

0.65

PhyloP100

-0.18

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

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