rs3740486

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-100990866-T-C
• chr10-100990866-T-A

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.1593-3T>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
• 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=-0.93).
• BP6: Variant 10-100990866-T-C is Benign according to our data. Variant chr10-100990866-T-C is described in ClinVar as Benign. ClinVar VariationId 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.

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.1593-3T>C		splice_region intron	N/A	NP_068602.2
	TWNK	NM_001163812.2		c.1593-3T>C		splice_region intron	N/A	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.231-3T>C		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.1593-3T>C		splice_region intron	N/A	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.1593-3T>C		splice_region intron	N/A	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000473656.5	TSL:2	c.231-3T>C		splice_region intron	N/A	ENSP00000494326.1	A0A2R8Y4V4

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

GnomAD2 exomes AF: 0.274 AC: 68978 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: 337139 AN: 1460270 Hom.: 44054 Cov.: 33 AF XY: 0.231 AC XY: 167802 AN XY: 726500

African (AFR) AF: 0.470 AC: 15710 AN: 33434

American (AMR) AF: 0.365 AC: 16339 AN: 44724

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

East Asian (EAS) AF: 0.554 AC: 21973 AN: 39684

South Asian (SAS) AF: 0.292 AC: 25152 AN: 86224

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

Middle Eastern (MID) AF: 0.210 AC: 1211 AN: 5764

European-Non Finnish (NFE) AF: 0.206 AC: 228672 AN: 1110568

Other (OTH) AF: 0.247 AC: 14895 AN: 60324

GnomAD4 genome AF: 0.288 AC: 43748 AN: 151840 Hom.: 7428 Cov.: 32 AF XY: 0.289 AC XY: 21484 AN XY: 74222

African (AFR) AF: 0.443 AC: 18292 AN: 41326

American (AMR) AF: 0.301 AC: 4592 AN: 15240

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

East Asian (EAS) AF: 0.542 AC: 2784 AN: 5140

South Asian (SAS) AF: 0.304 AC: 1461 AN: 4808

European-Finnish (FIN) AF: 0.173 AC: 1831 AN: 10594

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

European-Non Finnish (NFE) AF: 0.199 AC: 13555 AN: 67954

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

Alfa AF: 0.236 Hom.: 2144

Bravo AF: 0.310

Asia WGS AF: 0.422 AC: 1466 AN: 3478

EpiCase AF: 0.196

EpiControl AF: 0.204

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.93
CADD	Benign	6.3
DANN	Benign	0.38
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3740486; hg19: chr10-102750623; COSMIC: COSV54550548; COSMIC: COSV54550548;