rs757120802

Variant names:

• chr15-89333624-T-C
• rs757120802
• NM_002693.3:c.131A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_002693.3(POLG):​c.131A>G​(p.Gln44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,590,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q44H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: -0.467
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017874688).
• BP6: Variant 15-89333624-T-C is Benign according to our data. Variant chr15-89333624-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195177.

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.131A>G	p.Gln44Arg	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.186A>G	p.Ala62Ala	synonymous	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.131A>G	p.Gln44Arg	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.131A>G	p.Gln44Arg	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.131A>G	p.Gln44Arg	missense	Exon 2 of 23	ENSP00000399851.2	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.186A>G	p.Ala62Ala	synonymous	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 151958 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000197 AC: 43 AN: 218584 AF XY: 0.000173

Gnomad AFR exome AF: 0.000163

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000608

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000546

GnomAD4 exome AF: 0.0000563 AC: 81 AN: 1438256 Hom.: 0 Cov.: 32 AF XY: 0.0000559 AC XY: 40 AN XY: 715006

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

African (AFR) AF: 0.000125 AC: 4 AN: 31984

American (AMR) AF: 0.00130 AC: 56 AN: 43110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.0000512 AC: 2 AN: 39096

South Asian (SAS) AF: 0.0000354 AC: 3 AN: 84690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.0000118 AC: 13 AN: 1102214

Other (OTH) AF: 0.0000506 AC: 3 AN: 59330

⚠️ 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: 0.000362 AC: 55 AN: 152074 Hom.: 0 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74364

African (AFR) AF: 0.0000482 AC: 2 AN: 41514

American (AMR) AF: 0.00341 AC: 52 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000427

ExAC AF: 0.0000267 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	2	1	Progressive sclerosing poliodystrophy (3)
-	1	-	Inborn genetic diseases (1)
-	1	-	POLG-related disorder (1)
-	1	-	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	4.6
DANN	Benign	0.33
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.47
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.19
Sift	Benign	0.70	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.20		Gain of MoRF binding (P = 0.0084)
MVP		0.61
MPC		0.16
ClinPred		0.014	T
GERP RS		-0.97
PromoterAI		0.0031	Neutral
Varity_R		0.045
gMVP		0.13
Mutation Taster		=97/3	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: rs757120802; hg19: chr15-89876855;