10-100990864-C-T

Variant names:

• chr10-100990864-C-T
• rs3740485
• NM_021830.5:c.1593-5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021830.5(TWNK):​c.1593-5C>T 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 1,611,850 control chromosomes in the GnomAD database, including 51,486 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 (7425 hom., cov: 32)
  • Exomes 𝑓: 0.23 (44061 hom.)
• Consequence: TWNK NM_021830.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001431
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.118
• Publications: 21 publications found

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 Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial DNA depletion syndrome 7 (hepatocerebral type)

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial DNA depletion syndrome, hepatocerebrorenal form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Perrault syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-100990864-C-T is Benign according to our data. Variant chr10-100990864-C-T is described in ClinVar as Benign. ClinVar VariationId is 136589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWNK	NM_021830.5	MANE Select	c.1593-5C>T		splice_region intron	N/A	NP_068602.2
	TWNK	NM_001163812.2		c.1593-5C>T		splice_region intron	N/A	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.231-5C>T		splice_region intron	N/A	NP_001157285.1	A0A2R8Y4V4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWNK	ENST00000311916.8	TSL:1 MANE Select	c.1593-5C>T		splice_region intron	N/A	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.1593-5C>T		splice_region intron	N/A	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000473656.5	TSL:2	c.231-5C>T		splice_region intron	N/A	ENSP00000494326.1	A0A2R8Y4V4

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43670 AN: 151654 Hom.: 7400 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: 0.541

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.274 AC: 68976 AN: 251474 AF XY: 0.266

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 FIN exome AF: 0.174

Gnomad NFE exome AF: 0.202

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.231 AC: 337060 AN: 1460076 Hom.: 44061 Cov.: 33 AF XY: 0.231 AC XY: 167770 AN XY: 726410

African (AFR) AF: 0.470 AC: 15705 AN: 33430

American (AMR) AF: 0.365 AC: 16336 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3621 AN: 26130

East Asian (EAS) AF: 0.554 AC: 21968 AN: 39676

South Asian (SAS) AF: 0.292 AC: 25147 AN: 86212

European-Finnish (FIN) AF: 0.179 AC: 9566 AN: 53418

Middle Eastern (MID) AF: 0.210 AC: 1209 AN: 5760

European-Non Finnish (NFE) AF: 0.206 AC: 228625 AN: 1110424

Other (OTH) AF: 0.247 AC: 14883 AN: 60302

GnomAD4 genome AF: 0.288 AC: 43743 AN: 151774 Hom.: 7425 Cov.: 32 AF XY: 0.290 AC XY: 21482 AN XY: 74178

African (AFR) AF: 0.443 AC: 18284 AN: 41294

American (AMR) AF: 0.301 AC: 4593 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3472

East Asian (EAS) AF: 0.541 AC: 2786 AN: 5148

South Asian (SAS) AF: 0.304 AC: 1461 AN: 4810

European-Finnish (FIN) AF: 0.173 AC: 1831 AN: 10566

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13555 AN: 67940

Other (OTH) AF: 0.267 AC: 562 AN: 2106

Alfa AF: 0.233 Hom.: 4378

Bravo AF: 0.310

Asia WGS AF: 0.422 AC: 1466 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.204

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive cerebellar ataxia (1)
-	-	1	Infantile onset spinocerebellar ataxia (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 (1)
-	-	1	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.58
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs3740485; hg19: chr10-102750621; COSMIC: COSV54550546; COSMIC: COSV54550546;