15-89334628-G-A

Position:

• chr15-89334628-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002693.3(POLG):​c.-160+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.021 in 152,578 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (96 hom., cov: 34)
  • Exomes 𝑓: 0.0097 (0 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.141

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-89334628-G-A is Benign according to our data. Variant chr15-89334628-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1196941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLG	NM_002693.3	c.-160+45C>T		intron_variant		ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.-160+57C>T		intron_variant			NP_001119603.1
POLGARF	NM_001406557.1	c.-105+57C>T		intron_variant
POLG-DT	NR_186332.1	n.142G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.-160+45C>T		intron_variant		1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3202 AN: 152160 Hom.: 96 Cov.: 34

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0667

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.0839

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0332

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0162

Gnomad OTH AF: 0.0167

GnomAD4 exome AF: 0.00968 AC: 3 AN: 310 Hom.: 0 Cov.: 0 AF XY: 0.00870 AC XY: 2 AN XY: 230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0210 AC: 3203 AN: 152268 Hom.: 96 Cov.: 34 AF XY: 0.0234 AC XY: 1743 AN XY: 74456

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.0666

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.0842

Gnomad4 SAS AF: 0.00807

Gnomad4 FIN AF: 0.0332

Gnomad4 NFE AF: 0.0162

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0196 Hom.: 11

Bravo AF: 0.0248

Asia WGS AF: 0.0330 AC: 115 AN: 3470

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	9.2
DANN	Benign	0.93
RBP_binding_hub_radar		0.91
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2286353; hg19: chr15-89877859;