NM_021830.5:c.-592C>T

Variant names:

• chr10-100987619-C-T
• rs774214514
• NM_021830.5:c.-592C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021830.5(TWNK):​c.-592C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000316 in 924,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: TWNK NM_021830.5 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00002773
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -1.30
• Publications: 0 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]

MRPL43 (HGNC:14517): (mitochondrial ribosomal protein L43) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. This gene and the gene for a semaphorin class 4 protein (SEMA4G) overlap at map location 10q24.31 and are transcribed in opposite directions. Sequence analysis identified multiple transcript variants encoding at least four different protein isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).

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.-592C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_068602.2
	TWNK	NM_021830.5	MANE Select	c.-592C>T		5_prime_UTR	Exon 1 of 5	NP_068602.2
	TWNK	NM_001163812.2		c.-592C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001157284.1	Q96RR1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TWNK	ENST00000311916.8	TSL:1 MANE Select	c.-592C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.-592C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000311916.8	TSL:1 MANE Select	c.-592C>T		5_prime_UTR	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152092 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000332 AC: 256 AN: 771954 Hom.: 0 Cov.: 10 AF XY: 0.000332 AC XY: 129 AN XY: 389000

African (AFR) AF: 0.000109 AC: 2 AN: 18326

American (AMR) AF: 0.000516 AC: 10 AN: 19384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15728

East Asian (EAS) AF: 0.00 AC: 0 AN: 32426

South Asian (SAS) AF: 0.00 AC: 0 AN: 51936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2636

European-Non Finnish (NFE) AF: 0.000425 AC: 240 AN: 565264

Other (OTH) AF: 0.000109 AC: 4 AN: 36546

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12 AN XY: 74296

African (AFR) AF: 0.000169 AC: 7 AN: 41406

American (AMR) AF: 0.000262 AC: 4 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000694 Hom.: 0

Bravo AF: 0.000329

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C1849096:Infantile onset spinocerebellar ataxia;C4015307:Perrault syndrome 5 (1)
-	1	-	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.89
PhyloP100		-1.3
PromoterAI		0.0092	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs774214514; hg19: chr10-102747376;