rs2307441

Variant names:

• chr15-89318595-T-C
• rs2307441
• NM_002693.3:c.3428A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89318595-T-C
• chr15-89318595-T-A
• chr15-89318595-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BA1 BS2

This summary comes from the ClinGen Evidence Repository: The c.3428 A>G (p.E1143G) variant in POLG has been reported 2.881 % in gnomAD (BA1). It is also seen in the homozygous state in 175 individuals in gnomAD and 65 in ExAC (BS2). In summary, this variant meets criteria to be classified as benign for primary mitochondrial disease inherited in a recessive manner. ntDNA Mitochondrial ACMG-AMP Criteria for POLG applied: BA1 & BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA248706/MONDO:0044970/014

• Frequency:
  • Genomes: 𝑓 0.026 (113 hom., cov: 32)
  • Exomes 𝑓: 0.038 (1297 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign reviewed by expert panel B:24 O:1
• Conservation: PhyloP100: 1.90
• Publications: 91 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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.3428A>G	p.Glu1143Gly	missense	Exon 21 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3428A>G	p.Glu1143Gly	missense	Exon 21 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.3428A>G	p.Glu1143Gly	missense	Exon 21 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3428A>G	p.Glu1143Gly	missense	Exon 21 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.3428A>G	p.Glu1143Gly	missense	Exon 21 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.0265 AC: 4037 AN: 152154 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0614

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0342

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0421

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0287 AC: 7222 AN: 251414 AF XY: 0.0293

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.0603

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0317

Gnomad NFE exome AF: 0.0416

Gnomad OTH exome AF: 0.0293

GnomAD4 exome AF: 0.0383 AC: 56044 AN: 1461804 Hom.: 1297 Cov.: 32 AF XY: 0.0379 AC XY: 27594 AN XY: 727206

African (AFR) AF: 0.00409 AC: 137 AN: 33478

American (AMR) AF: 0.0110 AC: 490 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0636 AC: 1661 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0177 AC: 1528 AN: 86250

European-Finnish (FIN) AF: 0.0331 AC: 1767 AN: 53412

Middle Eastern (MID) AF: 0.0213 AC: 122 AN: 5724

European-Non Finnish (NFE) AF: 0.0432 AC: 48003 AN: 1111994

Other (OTH) AF: 0.0386 AC: 2333 AN: 60386

GnomAD4 genome AF: 0.0265 AC: 4035 AN: 152272 Hom.: 113 Cov.: 32 AF XY: 0.0260 AC XY: 1938 AN XY: 74454

African (AFR) AF: 0.00597 AC: 248 AN: 41560

American (AMR) AF: 0.0133 AC: 203 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0614 AC: 213 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4828

European-Finnish (FIN) AF: 0.0342 AC: 363 AN: 10606

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0421 AC: 2863 AN: 68014

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

Alfa AF: 0.0372 Hom.: 498

Bravo AF: 0.0243

TwinsUK AF: 0.0378 AC: 140

ALSPAC AF: 0.0413 AC: 159

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0388 AC: 334

ExAC AF: 0.0281 AC: 3410

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0401

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	7	not provided (7)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial disease (1)
-	-	1	POLG-Related Spectrum Disorders (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)
-	-	-	Association with valproate-induced liver toxicity (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Benign	0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.9
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.58
Sift	Benign	0.038	D
Sift4G	Benign	0.16	T
Polyphen		0.81	P
Vest4		0.15
MPC		0.18
ClinPred		0.030	T
GERP RS		1.5
Varity_R		0.24
gMVP		0.66
Mutation Taster		=87/13	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2307441; hg19: chr15-89861826; COSMIC: COSV51520517; COSMIC: COSV51520517;