rs11542131

Variant names:

• chr10-100994031-C-G
• rs11542131
• NM_021830.5:c.*521C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-100994031-C-G
• chr10-100994031-C-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.*521C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0796 in 170,708 control chromosomes in the GnomAD database, including 714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (640 hom., cov: 32)
  • Exomes 𝑓: 0.075 (74 hom.)
• Consequence: TWNK NM_021830.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0320
• Publications: 5 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=-0.85).
• BP6: Variant 10-100994031-C-G is Benign according to our data. Variant chr10-100994031-C-G is described in ClinVar as Benign. ClinVar VariationId is 298513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 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.*521C>G		3_prime_UTR	Exon 5 of 5	NP_068602.2
	TWNK	NM_001163812.2		c.*871C>G		3_prime_UTR	Exon 5 of 5	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.*521C>G		3_prime_UTR	Exon 5 of 5	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.*521C>G		3_prime_UTR	Exon 5 of 5	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.*871C>G		3_prime_UTR	Exon 5 of 5	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000643860.1		n.*1100C>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000494389.1	Q96RR1-3

Frequencies

GnomAD3 genomes AF: 0.0802 AC: 12199 AN: 152084 Hom.: 640 Cov.: 32

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.0440

Gnomad AMR AF: 0.0787

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.0644

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.0748 AC: 1385 AN: 18506 Hom.: 74 Cov.: 0 AF XY: 0.0715 AC XY: 701 AN XY: 9810

African (AFR) AF: 0.00532 AC: 1 AN: 188

American (AMR) AF: 0.0673 AC: 190 AN: 2824

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 16 AN: 218

East Asian (EAS) AF: 0.0180 AC: 17 AN: 946

South Asian (SAS) AF: 0.0545 AC: 148 AN: 2718

European-Finnish (FIN) AF: 0.0636 AC: 30 AN: 472

Middle Eastern (MID) AF: 0.0714 AC: 3 AN: 42

European-Non Finnish (NFE) AF: 0.0882 AC: 909 AN: 10304

Other (OTH) AF: 0.0894 AC: 71 AN: 794

GnomAD4 genome AF: 0.0802 AC: 12207 AN: 152202 Hom.: 640 Cov.: 32 AF XY: 0.0769 AC XY: 5724 AN XY: 74400

African (AFR) AF: 0.0255 AC: 1060 AN: 41534

American (AMR) AF: 0.0786 AC: 1202 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 515 AN: 3472

East Asian (EAS) AF: 0.0233 AC: 121 AN: 5184

South Asian (SAS) AF: 0.0643 AC: 310 AN: 4822

European-Finnish (FIN) AF: 0.0839 AC: 889 AN: 10594

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7842 AN: 67996

Other (OTH) AF: 0.0995 AC: 210 AN: 2110

Alfa AF: 0.0913 Hom.: 99

Bravo AF: 0.0792

Asia WGS AF: 0.0300 AC: 104 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	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	-0.85
CADD	Benign	2.9
DANN	Benign	0.53
PhyloP100		-0.032
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs11542131; hg19: chr10-102753788;