rs1555453424

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002693.3(POLG):​c.1885G>C​(p.Asp629His) 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 (★).

Frequency

Genomes: not found (cov: 32)

Consequence

POLG
NM_002693.3 missense

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
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 Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.876

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkc.1885G>C p.Asp629His missense_variant 10/23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.1885G>C p.Asp629His missense_variant 10/23 NP_001119603.1 P54098E5KNU5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.1885G>C p.Asp629His missense_variant 10/231 NM_002693.3 ENSP00000268124.5 P54098

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2024This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 629 of the POLG protein (p.Asp629His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLG-related conditions. ClinVar contains an entry for this variant (Variation ID: 458699). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLG protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.60
D;D
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-2.9
D;D
REVEL
Pathogenic
0.71
Sift
Benign
0.042
D;D
Sift4G
Uncertain
0.048
D;D
Polyphen
1.0
D;D
Vest4
0.85
MutPred
0.41
Loss of ubiquitination at K633 (P = 0.0288);Loss of ubiquitination at K633 (P = 0.0288);
MVP
0.96
MPC
0.70
ClinPred
0.97
D
GERP RS
5.0
Varity_R
0.51
gMVP
0.77

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

LitVar

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

Other links and lift over

dbSNP: rs1555453424; hg19: chr15-89868745; API