rs753858440

Variant names:

• chr15-89333295-C-T
• rs753858440
• NM_002693.3:c.460G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-89333295-C-T
• chr15-89333295-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_002693.3(POLG):​c.460G>A​(p.Ala154Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,552,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:10
• Conservation: PhyloP100: 7.65
• Publications: 3 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

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

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.460G>A	p.Ala154Thr	missense	Exon 2 of 23	NP_002684.1	P54098
	POLGARF	NM_001430120.1	MANE Select	c.515G>A	p.Gly172Asp	missense	Exon 1 of 2	NP_001417049.1	A0A3B3IS91
	POLG	NM_001126131.2		c.460G>A	p.Ala154Thr	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.460G>A	p.Ala154Thr	missense	Exon 2 of 23	ENSP00000268124.5	P54098
	POLGARF	ENST00000706918.1	MANE Select	c.515G>A	p.Gly172Asp	missense	Exon 1 of 2	ENSP00000516626.1	A0A3B3IS91
	POLG	ENST00000442287.6	TSL:1	c.460G>A	p.Ala154Thr	missense	Exon 2 of 23	ENSP00000399851.2	P54098

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152252 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000867 AC: 14 AN: 161510 AF XY: 0.000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000878 AC: 123 AN: 1400612 Hom.: 0 Cov.: 31 AF XY: 0.0000883 AC XY: 61 AN XY: 691010

African (AFR) AF: 0.0000629 AC: 2 AN: 31804

American (AMR) AF: 0.0000803 AC: 3 AN: 37374

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24788

East Asian (EAS) AF: 0.00 AC: 0 AN: 36328

South Asian (SAS) AF: 0.0000370 AC: 3 AN: 81118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45558

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5662

European-Non Finnish (NFE) AF: 0.0000981 AC: 106 AN: 1080128

Other (OTH) AF: 0.000121 AC: 7 AN: 57852

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152252 Hom.: 0 Cov.: 34 AF XY: 0.0000672 AC XY: 5 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41470

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.0000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000682 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Progressive sclerosing poliodystrophy (2)
-	1	-	Failure to thrive (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Mitochondrial DNA depletion syndrome 1 (1)
-	1	-	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.63
Sift	Benign	0.24	T
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.47		Loss of stability (P = 0.1206)
MVP		0.95
MPC		0.63
ClinPred		0.77	D
GERP RS		3.9
PromoterAI		0.013	Neutral
Varity_R		0.26
gMVP		0.70
Mutation Taster		=58/42	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: rs753858440; hg19: chr15-89876526; COSMIC: COSV105090744;