rs774459114

chr15-89333726-G-Achr15-89333726-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002693.3(POLG):c.29C>T(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,535,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. A10A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.223

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046337098).
• BP6: Variant 15-89333726-G-A is Benign according to our data. Variant chr15-89333726-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458708.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.29C>T	p.Ala10Val	missense_variant	2/23	ENST00000268124.11
POLGARF	NM_001406557.1	c.84C>T	p.Gly28=	synonymous_variant	2/23
POLG	NM_001126131.2	c.29C>T	p.Ala10Val	missense_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.29C>T	p.Ala10Val	missense_variant	2/23	1	NM_002693.3	P1
POLGARF	ENST00000706918.1	c.84C>T	p.Gly28=	synonymous_variant	1/2			P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000107 AC: 14 AN: 130834 Hom.: 0 AF XY: 0.0000838 AC XY: 6 AN XY: 71582

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: 0.00235

Gnomad NFE exome AF: 0.0000202

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000954 AC: 132 AN: 1383644 Hom.: 0 Cov.: 32 AF XY: 0.000111 AC XY: 76 AN XY: 682914

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: 0.00264

Gnomad4 NFE exome AF: 0.0000371

Gnomad4 OTH exome AF: 0.0000519

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74486

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000158 AC: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Progressive sclerosing poliodystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Benign	0.031
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.48	N
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.046	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.60	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.12	N;N
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.042	D;D
Polyphen		0.76	P;P
Vest4		0.27
MutPred		0.19		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.83
MPC		0.35
ClinPred		0.18	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.34

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: rs774459114; hg19: chr15-89876957;