rs3824783

Positions:

• chr10-100991094-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.677

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 -14 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 id is 1252118.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
TWNK	NM_021830.5	c.1734+84G>A		intron_variant		ENST00000311916.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TWNK	ENST00000311916.8	c.1734+84G>A		intron_variant		1	NM_021830.5	P1

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

Gnomad4 AFR exome AF: 0.471

Gnomad4 AMR exome AF: 0.364

Gnomad4 ASJ exome AF: 0.139

Gnomad4 EAS exome AF: 0.553

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.206

Gnomad4 OTH exome AF: 0.246

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

Gnomad4 AFR AF: 0.445

Gnomad4 AMR AF: 0.304

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.546

Gnomad4 SAS AF: 0.305

Gnomad4 FIN AF: 0.173

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.268

Alfa AF: 0.262 Hom.: 1278

Bravo AF: 0.310

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs3824783; hg19: chr10-102750851; COSMIC: COSV54550418; COSMIC: COSV54550418;