rs990343459

Positions:

• chr15-89319326-C-G
• chr15-89319326-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002693.3(POLG):​c.3006G>C​(p.Glu1002Asp) variant causes a missense change involving the alteration of a non-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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.525

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.3006G>C	p.Glu1002Asp	missense_variant	19/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.*2278G>C		3_prime_UTR_variant	19/23		NP_001393486.1
POLG	NM_001126131.2	c.3006G>C	p.Glu1002Asp	missense_variant	19/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3006G>C	p.Glu1002Asp	missense_variant	19/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 04, 2024

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Progressive sclerosing poliodystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1002 of the POLG protein (p.Glu1002Asp). 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: 570708). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POLG protein function. 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	Benign	0.33
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.92	N;N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.015	D;D
Sift4G	Benign	0.17	T;T
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.51		Gain of MoRF binding (P = 0.1055);Gain of MoRF binding (P = 0.1055);
MVP		0.95
MPC		0.61
ClinPred		0.77	D
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.28
gMVP		0.69

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

Other links and lift over

dbSNP: rs990343459; hg19: chr15-89862557;