10-100987903-CTG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_021830.5(TWNK):​c.-304_-303del variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 599,416 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00061 ( 2 hom. )

Consequence

TWNK
NM_021830.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.777
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6
Variant 10-100987903-CTG-C is Benign according to our data. Variant chr10-100987903-CTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 298490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00394 (600/152236) while in subpopulation AFR AF= 0.0139 (578/41518). AF 95% confidence interval is 0.013. There are 5 homozygotes in gnomad4. There are 275 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TWNKNM_021830.5 linkuse as main transcriptc.-304_-303del 5_prime_UTR_variant 1/5 ENST00000311916.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TWNKENST00000311916.8 linkuse as main transcriptc.-304_-303del 5_prime_UTR_variant 1/51 NM_021830.5 P1Q96RR1-1

Frequencies

GnomAD3 genomes
AF:
0.00394
AC:
599
AN:
152118
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0139
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000917
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00191
GnomAD4 exome
AF:
0.000615
AC:
275
AN:
447180
Hom.:
2
AF XY:
0.000646
AC XY:
152
AN XY:
235282
show subpopulations
Gnomad4 AFR exome
AF:
0.0142
Gnomad4 AMR exome
AF:
0.000381
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00141
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000371
Gnomad4 OTH exome
AF:
0.000768
GnomAD4 genome
AF:
0.00394
AC:
600
AN:
152236
Hom.:
5
Cov.:
32
AF XY:
0.00369
AC XY:
275
AN XY:
74434
show subpopulations
Gnomad4 AFR
AF:
0.0139
Gnomad4 AMR
AF:
0.000915
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00189
Bravo
AF:
0.00459
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive cerebellar ataxia Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Ataxia Neuropathy Spectrum Disorders Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Mitochondrial DNA depletion syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Progressive external ophthalmoplegia with mitochondrial DNA deletions Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 29, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146265037; hg19: chr10-102747660; API