rs587780421

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000268124.11(POLG):​c.3293A>T​(p.Asn1098Ile) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1098T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

POLG
ENST00000268124.11 missense

Scores

16
2
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49
Variant links:
Genes affected
POLG (HGNC:9179): (DNA polymerase gamma, catalytic subunit) Mitochondrial DNA polymerase is heterotrimeric, consisting of a homodimer of accessory subunits plus a catalytic subunit. The protein encoded by this gene is the catalytic subunit of mitochondrial DNA polymerase. The encoded protein contains a polyglutamine tract near its N-terminus that may be polymorphic. Defects in this gene are a cause of progressive external ophthalmoplegia with mitochondrial DNA deletions 1 (PEOA1), sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO), Alpers-Huttenlocher syndrome (AHS), and mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE). Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000268124.11
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr15-89318729-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1699813.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkuse as main transcriptc.3293A>T p.Asn1098Ile missense_variant 21/23 ENST00000268124.11 NP_002684.1
POLGARFNM_001406557.1 linkuse as main transcriptc.*2565A>T 3_prime_UTR_variant 21/23 NP_001393486.1
POLGNM_001126131.2 linkuse as main transcriptc.3293A>T p.Asn1098Ile missense_variant 21/23 NP_001119603.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.3293A>T p.Asn1098Ile missense_variant 21/231 NM_002693.3 ENSP00000268124 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Progressive sclerosing poliodystrophy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 01, 2018The NM_002693.2:c.3293A>T (NP_002684.1:p.Asn1098Ile) [GRCH38: NC_000015.10:g.89318730T>A] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PM2:This variant is absent in key population databases. PP2:This is a missense variant in POLG with a low rate of benign and high rate of pathogenic missense variations. PP3:Computational evidence/predictors indicate the variant has deleterious effect on POLG structure, function, or protein-protein interaction. Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
34
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
1.0
.;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.5
H;H
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-8.5
D;D
REVEL
Pathogenic
0.94
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.99
MutPred
0.93
Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);
MVP
0.99
MPC
0.74
ClinPred
1.0
D
GERP RS
5.3
Varity_R
0.96
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.36
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.36
Position offset: -14

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780421; hg19: chr15-89861961; API