rs2307439

Positions:

• chr15-89323966-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002693.3(POLG):​c.2071-65G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,536,812 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0032 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (41 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.467

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:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00324 (494/152346) while in subpopulation EAS AF= 0.0494 (256/5184). AF 95% confidence interval is 0.0444. There are 9 homozygotes in gnomad4. There are 245 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2071-65G>A		intron_variant		ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2071-65G>A		intron_variant			NP_001119603.1
POLGARF	NM_001406557.1	c.*1343-65G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2071-65G>A		intron_variant		1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.00324 AC: 493 AN: 152228 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0491

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.00331 AC: 4576 AN: 1384466 Hom.: 41 Cov.: 23 AF XY: 0.00328 AC XY: 2270 AN XY: 692798

Gnomad4 AFR exome AF: 0.000907

Gnomad4 AMR exome AF: 0.000382

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0466

Gnomad4 SAS exome AF: 0.00416

Gnomad4 FIN exome AF: 0.00340

Gnomad4 NFE exome AF: 0.00180

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.00324 AC: 494 AN: 152346 Hom.: 9 Cov.: 33 AF XY: 0.00329 AC XY: 245 AN XY: 74498

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.00414

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00288

Asia WGS AF: 0.0300 AC: 105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	9.8
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2307439; hg19: chr15-89867197; COSMIC: COSV51521773; COSMIC: COSV51521773;