15-89333627-T-C

Variant names:

• chr15-89333627-T-C
• rs28567406
• NM_002693.3:c.128A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002693.3(POLG):​c.128A>G​(p.Gln43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00538 in 1,580,742 control chromosomes in the GnomAD database, including 85 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0044 (51 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -6.18
• Publications: 9 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030815005).
• BP6: Variant 15-89333627-T-C is Benign according to our data. Variant chr15-89333627-T-C is described in ClinVar as Benign. ClinVar VariationId is 129989.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2169/151788) while in subpopulation AFR AF = 0.0412 (1708/41428). AF 95% confidence interval is 0.0396. There are 34 homozygotes in GnomAd4. There are 998 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.128A>G	p.Gln43Arg	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.183A>G	p.Ala61Ala	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.128A>G	p.Gln43Arg	missense	Exon 2 of 23	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.128A>G	p.Gln43Arg	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.128A>G	p.Gln43Arg	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.183A>G	p.Ala61Ala	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2151 AN: 151676 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00526

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00523 AC: 1057 AN: 202064 AF XY: 0.00487

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00475

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00443 AC: 6336 AN: 1428954 Hom.: 51 Cov.: 32 AF XY: 0.00437 AC XY: 3098 AN XY: 709510

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0425 AC: 1386 AN: 32602

American (AMR) AF: 0.00391 AC: 162 AN: 41442

Ashkenazi Jewish (ASJ) AF: 0.00580 AC: 149 AN: 25700

East Asian (EAS) AF: 0.00308 AC: 118 AN: 38292

South Asian (SAS) AF: 0.00587 AC: 493 AN: 83940

European-Finnish (FIN) AF: 0.00124 AC: 55 AN: 44444

Middle Eastern (MID) AF: 0.0104 AC: 59 AN: 5676

European-Non Finnish (NFE) AF: 0.00312 AC: 3425 AN: 1097614

Other (OTH) AF: 0.00825 AC: 489 AN: 59244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0143 AC: 2169 AN: 151788 Hom.: 34 Cov.: 33 AF XY: 0.0135 AC XY: 998 AN XY: 74190

African (AFR) AF: 0.0412 AC: 1708 AN: 41428

American (AMR) AF: 0.00525 AC: 80 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3466

East Asian (EAS) AF: 0.00619 AC: 32 AN: 5166

South Asian (SAS) AF: 0.00623 AC: 30 AN: 4818

European-Finnish (FIN) AF: 0.00114 AC: 12 AN: 10542

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.00363 AC: 246 AN: 67812

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.00868 Hom.: 2

Bravo AF: 0.0161

ExAC AF: 0.00511 AC: 580

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	POLG-Related Spectrum Disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	1.1
DANN	Benign	0.081
DEOGEN2	Benign	0.19	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.0	N
PhyloP100		-6.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.19	N
REVEL	Uncertain	0.30
Sift	Benign	0.34	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.52
MPC		0.16
ClinPred		0.014	T
GERP RS		-1.0
PromoterAI		-0.0085	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.12
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs28567406; hg19: chr15-89876858; COSMIC: COSV51520068; COSMIC: COSV51520068;