rs3740487

Variant names:

• chr10-100991026-C-A
• rs3740487
• ENST00000370228.2:c.*1C>A

Your query was ambiguous. Multiple possible variants found:

• chr10-100991026-C-A
• chr10-100991026-C-T

Variant summary

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

The NM_001163812.2(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 NM_001163812.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.952
• Publications: 29 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=-0.81).
• BP6: Variant 10-100991026-C-A is Benign according to our data. Variant chr10-100991026-C-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163812.2. 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.1734+16C>A		intron	N/A	NP_068602.2
	TWNK	NM_001163812.2		c.*1C>A		3_prime_UTR	Exon 4 of 5	NP_001157284.1
	TWNK	NM_001163814.2		c.*1C>A		3_prime_UTR	Exon 4 of 5	NP_001157286.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWNK	ENST00000370228.2	TSL:1	c.*1C>A		3_prime_UTR	Exon 4 of 5	ENSP00000359248.1
	TWNK	ENST00000311916.8	TSL:1 MANE Select	c.1734+16C>A		intron	N/A	ENSP00000309595.2
	TWNK	ENST00000476766.5	TSL:3	c.*1C>A		3_prime_UTR	Exon 4 of 5	ENSP00000496012.1

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

GnomAD2 exomes AF: 0.274 AC: 68942 AN: 251318 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: 0.246

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

African (AFR) AF: 0.470 AC: 15731 AN: 33476

American (AMR) AF: 0.365 AC: 16330 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3624 AN: 26136

East Asian (EAS) AF: 0.554 AC: 21979 AN: 39696

South Asian (SAS) AF: 0.292 AC: 25160 AN: 86256

European-Finnish (FIN) AF: 0.179 AC: 9561 AN: 53398

Middle Eastern (MID) AF: 0.211 AC: 1207 AN: 5732

European-Non Finnish (NFE) AF: 0.206 AC: 229358 AN: 1111842

Other (OTH) AF: 0.247 AC: 14925 AN: 60390

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

African (AFR) AF: 0.445 AC: 18458 AN: 41478

American (AMR) AF: 0.304 AC: 4646 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 483 AN: 3470

East Asian (EAS) AF: 0.544 AC: 2808 AN: 5158

South Asian (SAS) AF: 0.305 AC: 1471 AN: 4826

European-Finnish (FIN) AF: 0.174 AC: 1839 AN: 10584

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

European-Non Finnish (NFE) AF: 0.200 AC: 13595 AN: 67994

Other (OTH) AF: 0.269 AC: 567 AN: 2106

Alfa AF: 0.205 Hom.: 2813

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
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.0
DANN	Benign	0.69
PhyloP100		0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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