chr15-89318599-G-C

Position:

• chr15-89318599-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002693.3(POLG):​c.3424C>G​(p.Arg1142Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1142Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42031822).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.3424C>G	p.Arg1142Gly	missense_variant	21/23	ENST00000268124.11	NP_002684.1
POLGARF	NM_001406557.1	c.*2696C>G		3_prime_UTR_variant	21/23		NP_001393486.1
POLG	NM_001126131.2	c.3424C>G	p.Arg1142Gly	missense_variant	21/23		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3424C>G	p.Arg1142Gly	missense_variant	21/23	1	NM_002693.3	ENSP00000268124	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 11, 2017

The R1142G variant in the POLG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1142G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1142G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1142G as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D
Eigen	Benign	-0.077
Eigen_PC	Benign	0.068
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	.;D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.42	T;T
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.69	N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.29	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.36	B;B
Vest4		0.53
MutPred		0.45		Loss of helix (P = 0.0626);Loss of helix (P = 0.0626);
MVP		0.91
MPC		0.35
ClinPred		0.43	T
GERP RS		3.2
Varity_R		0.28
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2307442; hg19: chr15-89861830;