10-100990866-T-C

Variant names:

• chr10-100990866-T-C
• rs3740486
• NM_021830.5:c.1593-3T>C

Variant summary

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

The NM_021830.5(TWNK):​c.1593-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,110 control chromosomes in the GnomAD database, including 51,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7428 hom., cov: 32)
  • Exomes 𝑓: 0.23 (44054 hom.)
• Consequence: TWNK NM_021830.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004419
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.152

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=-0.93).
• BP6: Variant 10-100990866-T-C is Benign according to our data. Variant chr10-100990866-T-C is described in ClinVar as [Benign]. Clinvar id is 136590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1593-3T>C		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000311916.8	NP_068602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWNK	ENST00000311916.8	c.1593-3T>C		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43675 AN: 151720 Hom.: 7403 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.301

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.264

GnomAD3 exomes AF: 0.274 AC: 68978 AN: 251474 Hom.: 11215 AF XY: 0.266 AC XY: 36087 AN XY: 135910

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: 0.247

GnomAD4 exome AF: 0.231 AC: 337139 AN: 1460270 Hom.: 44054 Cov.: 33 AF XY: 0.231 AC XY: 167802 AN XY: 726500

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: 0.288 AC: 43748 AN: 151840 Hom.: 7428 Cov.: 32 AF XY: 0.289 AC XY: 21484 AN XY: 74222

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.542

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.199

Gnomad4 OTH AF: 0.267

Alfa AF: 0.233 Hom.: 2060

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

Jul 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2011

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive cerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Infantile onset spinocerebellar ataxia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.3
DANN	Benign	0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.052
SpliceAI score (max)		0.030		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: rs3740486; hg19: chr10-102750623; COSMIC: COSV54550548; COSMIC: COSV54550548;