10-100987606-G-T

Variant names:

• chr10-100987606-G-T
• rs3740484
• NM_021830.5:c.-605G>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.-605G>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 0.336 in 1,081,648 control chromosomes in the GnomAD database, including 63,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9839 hom., cov: 32)
  • Exomes 𝑓: 0.33 (53769 hom.)
• Consequence: TWNK NM_021830.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.00
• Publications: 29 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=-0.99).
• BP6: Variant 10-100987606-G-T is Benign according to our data. Variant chr10-100987606-G-T is described in ClinVar as Benign. ClinVar VariationId is 136593.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 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.-605G>T		5_prime_UTR	Exon 1 of 5	NP_068602.2
	TWNK	NM_001163812.2		c.-605G>T		5_prime_UTR	Exon 1 of 5	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.-127G>T		5_prime_UTR	Exon 1 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.-605G>T		5_prime_UTR	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.-605G>T		5_prime_UTR	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
	TWNK	ENST00000473656.5	TSL:2	c.-127G>T		5_prime_UTR	Exon 1 of 5	ENSP00000494326.1	A0A2R8Y4V4

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53597 AN: 151796 Hom.: 9814 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.351

GnomAD4 exome AF: 0.333 AC: 309944 AN: 929734 Hom.: 53769 Cov.: 12 AF XY: 0.333 AC XY: 153977 AN XY: 462320

African (AFR) AF: 0.432 AC: 9261 AN: 21460

American (AMR) AF: 0.412 AC: 8346 AN: 20276

Ashkenazi Jewish (ASJ) AF: 0.289 AC: 4883 AN: 16890

East Asian (EAS) AF: 0.567 AC: 18841 AN: 33244

South Asian (SAS) AF: 0.335 AC: 18598 AN: 55550

European-Finnish (FIN) AF: 0.263 AC: 7865 AN: 29908

Middle Eastern (MID) AF: 0.278 AC: 822 AN: 2958

European-Non Finnish (NFE) AF: 0.321 AC: 226967 AN: 707840

Other (OTH) AF: 0.345 AC: 14361 AN: 41608

GnomAD4 genome AF: 0.353 AC: 53666 AN: 151914 Hom.: 9839 Cov.: 32 AF XY: 0.352 AC XY: 26104 AN XY: 74254

African (AFR) AF: 0.419 AC: 17360 AN: 41400

American (AMR) AF: 0.376 AC: 5739 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3468

East Asian (EAS) AF: 0.566 AC: 2903 AN: 5130

South Asian (SAS) AF: 0.347 AC: 1669 AN: 4812

European-Finnish (FIN) AF: 0.257 AC: 2724 AN: 10580

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21299 AN: 67928

Other (OTH) AF: 0.352 AC: 743 AN: 2110

Alfa AF: 0.332 Hom.: 6611

Bravo AF: 0.371

Asia WGS AF: 0.433 AC: 1505 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: 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	not specified (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	-0.99
CADD	Benign	0.39
DANN	Benign	0.29
PhyloP100		-3.0
PromoterAI		-0.11	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3740484; hg19: chr10-102747363;