15-89326965-C-T

Position:

• chr15-89326965-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_002693.3(POLG):​c.1532G>A​(p.Ser511Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.849

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809
• PP5: Variant 15-89326965-C-T is Pathogenic according to our data. Variant chr15-89326965-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13514.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.1532G>A	p.Ser511Asn	missense_variant	8/23	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.1532G>A	p.Ser511Asn	missense_variant	8/23		NP_001119603.1
POLGARF	NM_001406557.1	c.*804G>A		3_prime_UTR_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.1532G>A	p.Ser511Asn	missense_variant	8/23	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.86
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.19
Sift	Benign	0.36	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.45	P;P
Vest4		0.22
MutPred		0.69		Loss of phosphorylation at S511 (P = 0.0243);Loss of phosphorylation at S511 (P = 0.0243);
MVP		0.82
MPC		0.14
ClinPred		0.059	T
GERP RS		2.3
Varity_R		0.020
gMVP		0.22

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: rs121918055; hg19: chr15-89870196;