rs370231886

Variant names:

• chr10-100989262-A-G
• rs370231886
• NM_021830.5:c.1052A>G
• TWNK p.Asn351Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_021830.5(TWNK):​c.1052A>G​(p.Asn351Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: TWNK NM_021830.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.65
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_021830.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 36 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.6071 (below the threshold of 3.09). Trascript score misZ: 2.58 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial DNA depletion syndrome 7 (hepatocerebral type), autosomal dominant progressive external ophthalmoplegia, progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, Perrault syndrome, mitochondrial DNA depletion syndrome, hepatocerebrorenal form.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08390921).

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.1052A>G	p.Asn351Ser	missense	Exon 1 of 5	NP_068602.2
	TWNK	NM_001163812.2		c.1052A>G	p.Asn351Ser	missense	Exon 1 of 5	NP_001157284.1	Q96RR1-2
	TWNK	NM_001163813.2		c.-119-382A>G		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.1052A>G	p.Asn351Ser	missense	Exon 1 of 5	ENSP00000309595.2	Q96RR1-1
	TWNK	ENST00000370228.2	TSL:1	c.1052A>G	p.Asn351Ser	missense	Exon 1 of 5	ENSP00000359248.1	Q96RR1-2
	MRPL43	ENST00000858454.1		c.-186T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000528513.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251416 AF XY: 0.0000809

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79 AN XY: 727234

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74320

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.6
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.29
Sift	Benign	0.28	T
Sift4G	Benign	0.26	T
Varity_R		0.11
gMVP		0.52
Mutation Taster		=76/24	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs370231886;

hg19: chr10-102749019;