rs3176200

Positions:

• chr15-89323573-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_002693.3(POLG):​c.2158-62C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00091 in 1,104,964 control chromosomes in the GnomAD database, including 13 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 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (13 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000689 (105/152360) while in subpopulation EAS AF= 0.0191 (99/5188). AF 95% confidence interval is 0.016. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.2158-62C>T		intron_variant		ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.2158-62C>T		intron_variant			NP_001119603.1
POLGARF	NM_001406557.1	c.*1430-62C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.2158-62C>T		intron_variant		1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.000696 AC: 106 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000945 AC: 900 AN: 952604 Hom.: 13 Cov.: 13 AF XY: 0.000891 AC XY: 441 AN XY: 494776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.0000531

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.0000123

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000886 AC XY: 66 AN XY: 74512

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000805

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3176200; hg19: chr15-89866804;