rs121918045

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_002693.3(POLG):ā€‹c.8G>Cā€‹(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

4
9
6

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 1.16
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]
POLGARF (HGNC:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-89333747-C-G is Pathogenic according to our data. Variant chr15-89333747-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13498.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-89333747-C-G is described in UniProt as null. Variant chr15-89333747-C-G is described in UniProt as null.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkuse as main transcriptc.8G>C p.Arg3Pro missense_variant 2/23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkuse as main transcriptc.8G>C p.Arg3Pro missense_variant 2/23 NP_001119603.1 P54098E5KNU5
POLGARFNM_001406557.1 linkuse as main transcriptc.63G>C p.Pro21Pro synonymous_variant 2/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.8G>C p.Arg3Pro missense_variant 2/231 NM_002693.3 ENSP00000268124.5 P54098
POLGARFENST00000706918.1 linkuse as main transcriptc.63G>C p.Pro21Pro synonymous_variant 1/2 ENSP00000516626.1 A0A3B3IS91

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.23e-7
AC:
1
AN:
1382966
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
682508
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.27e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 01, 2001- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.38
T;T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.81
.;T
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.61
D;D
MetaSVM
Uncertain
0.33
D
MutationAssessor
Benign
1.1
L;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.1
N;N
REVEL
Pathogenic
0.65
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.025
D;D
Polyphen
0.97
D;D
Vest4
0.39
MutPred
0.75
Gain of ubiquitination at K8 (P = 0.0338);Gain of ubiquitination at K8 (P = 0.0338);
MVP
0.90
MPC
0.43
ClinPred
0.94
D
GERP RS
4.8
Varity_R
0.65
gMVP
0.52

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: rs121918045; hg19: chr15-89876978; API