rs3740487

chr10-100991026-C-Achr10-100991026-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000370228.2(TWNK):c.*1C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,613,746 control chromosomes in the GnomAD database, including 51,641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7580 hom., cov: 32)
  • Exomes 𝑓: 0.23 (44061 hom.)
• Consequence: TWNK ENST00000370228.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.952

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 10-100991026-C-A is Benign according to our data. Variant chr10-100991026-C-A is described in ClinVar as [Benign]. Clinvar id is 136591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TWNK	NM_021830.5	c.1734+16C>A		intron_variant		ENST00000311916.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWNK	ENST00000311916.8	c.1734+16C>A		intron_variant		1	NM_021830.5	P1

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43985 AN: 151996 Hom.: 7556 Cov.: 32

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.544

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.267

GnomAD3 exomes AF: 0.274 AC: 68942 AN: 251318 Hom.: 11208 AF XY: 0.266 AC XY: 36064 AN XY: 135830

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.374

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.550

Gnomad SAS exome AF: 0.294

Gnomad FIN exome AF: 0.174

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.231 AC: 337875 AN: 1461632 Hom.: 44061 Cov.: 33 AF XY: 0.231 AC XY: 168143 AN XY: 727116

Gnomad4 AFR exome AF: 0.470

Gnomad4 AMR exome AF: 0.365

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.554

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.179

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.290 AC: 44056 AN: 152114 Hom.: 7580 Cov.: 32 AF XY: 0.291 AC XY: 21642 AN XY: 74360

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.544

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.269

Alfa AF: 0.196 Hom.: 1902

Bravo AF: 0.310

Asia WGS AF: 0.422 AC: 1466 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.204

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	8.0
Dann	Benign	0.69

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

LitVar

Other links and lift over

dbSNP: rs3740487; hg19: chr10-102750783; COSMIC: COSV54550555; COSMIC: COSV54550555;