NM_002693.3:c.3482+6C>T

Variant names:

• chr15-89318535-G-A
• rs55779802
• NM_002693.3:c.3482+6C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_002693.3(POLG):​c.3482+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,611,858 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: POLG NM_002693.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001169
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5
• Conservation: PhyloP100: -0.685
• Publications: 2 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

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-89318535-G-A is Benign according to our data. Variant chr15-89318535-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138760.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.3482+6C>T		splice_region intron	N/A	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3482+6C>T		splice_region intron	N/A	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.3482+6C>T		splice_region intron	N/A	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3482+6C>T		splice_region intron	N/A	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.3482+6C>T		splice_region intron	N/A	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152238 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 250808 AF XY: 0.000221

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000119 AC: 173 AN: 1459502 Hom.: 2 Cov.: 31 AF XY: 0.000114 AC XY: 83 AN XY: 726106

African (AFR) AF: 0.00120 AC: 40 AN: 33408

American (AMR) AF: 0.000447 AC: 20 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00236 AC: 11 AN: 4666

European-Non Finnish (NFE) AF: 0.0000657 AC: 73 AN: 1111154

Other (OTH) AF: 0.000266 AC: 16 AN: 60214

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152356 Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74500

African (AFR) AF: 0.00123 AC: 51 AN: 41588

American (AMR) AF: 0.00144 AC: 22 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000226 Hom.: 0

Bravo AF: 0.000661

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Progressive sclerosing poliodystrophy (3)
-	-	2	not specified (2)
-	1	-	Hereditary spastic paraplegia (1)
-	-	1	Mitochondrial DNA depletion syndrome 4b (1)
-	1	-	not provided (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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.5
DANN	Benign	0.83
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.020
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: rs55779802; hg19: chr15-89861766;