15-89333588-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002693.3(POLG):​c.167C>A​(p.Pro56His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

POLG
NM_002693.3 missense

Scores

1
18

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.553
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08597532).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
POLGNM_002693.3 linkuse as main transcriptc.167C>A p.Pro56His missense_variant 2/23 ENST00000268124.11 NP_002684.1 P54098E5KNU5
POLGNM_001126131.2 linkuse as main transcriptc.167C>A p.Pro56His missense_variant 2/23 NP_001119603.1 P54098E5KNU5
POLGARFNM_001406557.1 linkuse as main transcriptc.222C>A p.Ala74Ala synonymous_variant 2/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
POLGENST00000268124.11 linkuse as main transcriptc.167C>A p.Pro56His missense_variant 2/231 NM_002693.3 ENSP00000268124.5 P54098
POLGARFENST00000706918.1 linkuse as main transcriptc.222C>A p.Ala74Ala synonymous_variant 1/2 ENSP00000516626.1 A0A3B3IS91

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1453840
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
723488
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:
0.00000271
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
13
DANN
Benign
0.82
DEOGEN2
Benign
0.30
T;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.33
.;T
M_CAP
Benign
0.071
D
MetaRNN
Benign
0.086
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.69
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.020
N;N
REVEL
Benign
0.14
Sift
Benign
0.10
T;T
Sift4G
Uncertain
0.038
D;D
Polyphen
0.35
B;B
Vest4
0.15
MutPred
0.17
Loss of glycosylation at P56 (P = 0.0062);Loss of glycosylation at P56 (P = 0.0062);
MVP
0.37
MPC
0.19
ClinPred
0.077
T
GERP RS
-1.9
Varity_R
0.063
gMVP
0.23

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: rs1022612492; hg19: chr15-89876819; COSMIC: COSV51522835; COSMIC: COSV51522835; API