rs368614463

Positions:

• chr15-89327197-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM5 BP4

The NM_002693.3(POLG):​c.1403A>G​(p.Asn468Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N468D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 7.57

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_002693.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-89327198-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 206596.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=15, Pathogenic=1, Likely_pathogenic=4, Likely_benign=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3717739).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1403A>G	p.Asn468Ser	missense_variant	7/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.*675A>G		3_prime_UTR_variant	7/23
POLG	NM_001126131.2	c.1403A>G	p.Asn468Ser	missense_variant	7/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1403A>G	p.Asn468Ser	missense_variant	7/23	1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251488 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000109 AC: 160 AN: 1461886 Hom.: 0 Cov.: 34 AF XY: 0.000106 AC XY: 77 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

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: 0.000138

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74382

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 11, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	p.Asn468Ser (AAT>AGT): c.1403 A>G in exon 7 of the POLG gene (NM_002693.2). The N468S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Another missense change at the same position (N468D) has been reported as a pathogenic POLG variant (Luoma et al., 2004; Schulte et al., 2009; Blok et al., 2009); however, none of these reports provide sufficient information to support N468D as pathogenic. The N468S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N468S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. However, missense variants in nearby residues (M464T, A467T) have been reported in the Human Gene Mutation Database in association with POLG-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. The variant is found in EPILEPSY,MITONUC-MITOP panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 28, 2020	- -

Progressive sclerosing poliodystrophy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.1403A>G (NP_002684.1:p.Asn468Ser) [GRCH38: NC_000015.10:g.89327197T>C] variant in POLG gene is interpretated to be a Uncertain Significance based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. PS1:This variation causes same amino-acid change as an established pathogenic variant. BS2:Observation of the variant in controls is inconsistent with penetrance of Mitochondrial DNA depletion syndrome 4A (Alpers type). Based on the evidence criteria codes applied, the variant is suggested to be Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 468 of the POLG protein (p.Asn468Ser). This variant is present in population databases (rs368614463, gnomAD 0.005%). 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: 206630). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Sep 13, 2023

Variant summary: POLG c.1403A>G (p.Asn468Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251488 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1403A>G in individuals affected with POLG-Related Spectrum Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 18, 2021

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2022

The c.1403A>G (p.N468S) alteration is located in exon 7 (coding exon 6) of the POLG gene. This alteration results from a A to G substitution at nucleotide position 1403, causing the asparagine (N) at amino acid position 468 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.041	D;D
Sift4G	Benign	0.31	T;T
Polyphen		0.068	B;B
Vest4		0.32
MVP		0.93
MPC		0.27
ClinPred		0.58	D
GERP RS		5.0
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.27
gMVP		0.17

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: rs368614463; hg19: chr15-89870428;