15-89333747-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_002693.3(POLG):​c.8G>A​(p.Arg3His) 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. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

2
10
7

Clinical Significance

Not reported in ClinVar

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]

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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;
PM5
Other missense variant is known to change same aminoacid residue: 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.35882133).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POLGNM_002693.3 linkc.8G>A p.Arg3His missense_variant Exon 2 of 23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkc.8G>A p.Arg3His missense_variant Exon 2 of 23 NP_001119603.1 P54098E5KNU5
POLGARFNM_001430120.1 linkc.63G>A p.Pro21Pro synonymous_variant Exon 1 of 2 NP_001417049.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkc.8G>A p.Arg3His missense_variant Exon 2 of 23 1 NM_002693.3 ENSP00000268124.5 P54098
POLGARFENST00000706918.1 linkc.63G>A p.Pro21Pro synonymous_variant Exon 1 of 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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.10
D
BayesDel_noAF
Benign
-0.090
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
T;T
Eigen
Uncertain
0.29
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Uncertain
0.24
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Uncertain
0.23
D
MutationAssessor
Benign
1.1
L;L
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.39
N;N
REVEL
Uncertain
0.40
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.027
D;D
Polyphen
0.99
D;D
Vest4
0.28
MutPred
0.34
Gain of ubiquitination at K8 (P = 0.0412);Gain of ubiquitination at K8 (P = 0.0412);
MVP
0.88
MPC
0.42
ClinPred
0.71
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.42
gMVP
0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-89876978; API