10-100987970-C-T

Variant names:

• chr10-100987970-C-T
• rs113159821
• NM_021830.5:c.-241C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021830.5(TWNK):​c.-241C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00224 in 634,762 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (1 hom.)
• Consequence: TWNK NM_021830.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.583
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-100987970-C-T is Benign according to our data. Variant chr10-100987970-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 298492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00666 (1013/152138) while in subpopulation AFR AF = 0.0235 (974/41496). AF 95% confidence interval is 0.0222. There are 14 homozygotes in GnomAd4. There are 478 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

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.-241C>T		5_prime_UTR	Exon 1 of 5	NP_068602.2
	TWNK	NM_001163812.2		c.-241C>T		5_prime_UTR	Exon 1 of 5	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.-120+357C>T		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.-241C>T		5_prime_UTR	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.-241C>T		5_prime_UTR	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000473656.5	TSL:2	c.-120+357C>T		intron	N/A	ENSP00000494326.1	A0A2R8Y4V4

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1006 AN: 152018 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000441

Gnomad OTH AF: 0.00432

GnomAD4 exome AF: 0.000841 AC: 406 AN: 482624 Hom.: 1 Cov.: 4 AF XY: 0.000693 AC XY: 178 AN XY: 256812

African (AFR) AF: 0.0223 AC: 304 AN: 13648

American (AMR) AF: 0.00153 AC: 40 AN: 26070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15108

East Asian (EAS) AF: 0.00 AC: 0 AN: 31610

South Asian (SAS) AF: 0.0000389 AC: 2 AN: 51442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30450

Middle Eastern (MID) AF: 0.000481 AC: 1 AN: 2078

European-Non Finnish (NFE) AF: 0.0000527 AC: 15 AN: 284762

Other (OTH) AF: 0.00160 AC: 44 AN: 27456

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152138 Hom.: 14 Cov.: 33 AF XY: 0.00643 AC XY: 478 AN XY: 74360

African (AFR) AF: 0.0235 AC: 974 AN: 41496

American (AMR) AF: 0.00177 AC: 27 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68004

Other (OTH) AF: 0.00427 AC: 9 AN: 2106

Alfa AF: 0.00341 Hom.: 3

Bravo AF: 0.00745

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive cerebellar ataxia (1)
-	-	1	Infantile onset spinocerebellar ataxia (1)
-	-	1	not provided (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	-0.95
CADD	Benign	4.2
DANN	Benign	0.84
PhyloP100		-0.58
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Other links and lift over

dbSNP: rs113159821; hg19: chr10-102747727;