10-100989165-A-G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_021830.5(TWNK):​c.955A>G​(p.Lys319Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K319R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TWNK
NM_021830.5 missense

Scores

7
8
3

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.99

Publications

8 publications found
Variant links:
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: Orphanet, Labcorp Genetics (formerly Invitae)
  • 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

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_021830.5
PM2
Very rare variant in population databases, with high coverage;
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 progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, mitochondrial DNA depletion syndrome 7 (hepatocerebral type), Perrault syndrome, autosomal dominant progressive external ophthalmoplegia, mitochondrial DNA depletion syndrome, hepatocerebrorenal form.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952
PP5
Variant 10-100989165-A-G is Pathogenic according to our data. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr10-100989165-A-G is described in CliVar as Pathogenic. Clinvar id is 4625.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TWNKNM_021830.5 linkc.955A>G p.Lys319Glu missense_variant Exon 1 of 5 ENST00000311916.8 NP_068602.2 Q96RR1-1E5KSY5Q9H6V3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TWNKENST00000311916.8 linkc.955A>G p.Lys319Glu missense_variant Exon 1 of 5 1 NM_021830.5 ENSP00000309595.2 Q96RR1-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3 Pathogenic:1
Jan 25, 2005
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.62
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.16
T;.
Eigen
Uncertain
0.64
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Benign
1.9
L;L
PhyloP100
9.0
PROVEAN
Uncertain
-2.5
D;D
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0060
D;D
Sift4G
Uncertain
0.017
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.81
Loss of MoRF binding (P = 0.0043);Loss of MoRF binding (P = 0.0043);
MVP
0.98
MPC
1.6
ClinPred
0.92
D
GERP RS
5.9
Varity_R
0.58
gMVP
0.88
Mutation Taster
=11/89
disease causing (ClinVar)

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

Publications

Other links and lift over

dbSNP: rs80356543; hg19: chr10-102748922; API