rs3824783

Variant names:

• chr10-100991094-G-A
• rs3824783
• NM_021830.5:c.1734+84G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-100991094-G-A
• chr10-100991094-G-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.1734+84G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,592,014 control chromosomes in the GnomAD database, including 50,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (7586 hom., cov: 32)
  • Exomes 𝑓: 0.23 (43259 hom.)
• Consequence: TWNK NM_021830.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.677
• Publications: 20 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: Orphanet, Labcorp Genetics (formerly Invitae)
• 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=-0.91).
• BP6: Variant 10-100991094-G-A is Benign according to our data. Variant chr10-100991094-G-A is described in ClinVar as Benign. ClinVar VariationId is 1252118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TWNK	NM_021830.5	c.1734+84G>A		intron_variant	Intron 4 of 4	ENST00000311916.8	NP_068602.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TWNK	ENST00000311916.8	c.1734+84G>A		intron_variant	Intron 4 of 4	1	NM_021830.5	ENSP00000309595.2

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43995 AN: 151980 Hom.: 7562 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: 0.546

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.266

GnomAD4 exome AF: 0.231 AC: 332428 AN: 1439916 Hom.: 43259 Cov.: 29 AF XY: 0.231 AC XY: 165121 AN XY: 714714

African (AFR) AF: 0.471 AC: 15542 AN: 33016

American (AMR) AF: 0.364 AC: 15895 AN: 43664

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3578 AN: 25774

East Asian (EAS) AF: 0.553 AC: 21765 AN: 39352

South Asian (SAS) AF: 0.292 AC: 24855 AN: 85220

European-Finnish (FIN) AF: 0.180 AC: 9202 AN: 51132

Middle Eastern (MID) AF: 0.209 AC: 969 AN: 4632

European-Non Finnish (NFE) AF: 0.206 AC: 225980 AN: 1097606

Other (OTH) AF: 0.246 AC: 14642 AN: 59520

GnomAD4 genome AF: 0.290 AC: 44066 AN: 152098 Hom.: 7586 Cov.: 32 AF XY: 0.291 AC XY: 21635 AN XY: 74342

African (AFR) AF: 0.445 AC: 18477 AN: 41482

American (AMR) AF: 0.304 AC: 4641 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3466

East Asian (EAS) AF: 0.546 AC: 2819 AN: 5166

South Asian (SAS) AF: 0.305 AC: 1468 AN: 4820

European-Finnish (FIN) AF: 0.173 AC: 1832 AN: 10584

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

European-Non Finnish (NFE) AF: 0.200 AC: 13591 AN: 67982

Other (OTH) AF: 0.268 AC: 567 AN: 2112

Alfa AF: 0.267 Hom.: 1362

Bravo AF: 0.310

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.61
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3824783; hg19: chr10-102750851; COSMIC: COSV54550418; COSMIC: COSV54550418;