rs780378329

chr15-89324236-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_002693.3(POLG):c.1950-9T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000571 in 1,611,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: POLG NM_002693.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.01659
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.13

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=-0.4).
• BP6: Variant 15-89324236-A-G is Benign according to our data. Variant chr15-89324236-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 206461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLG	NM_002693.3	c.1950-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000268124.11
POLGARF	NM_001406557.1	c.*1222-9T>C		splice_polypyrimidine_tract_variant, intron_variant
POLG	NM_001126131.2	c.1950-9T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLG	ENST00000268124.11	c.1950-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002693.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152274 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000203 AC: 5 AN: 246488 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133734

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000576 AC: 84 AN: 1459436 Hom.: 0 Cov.: 32 AF XY: 0.0000551 AC XY: 40 AN XY: 726032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000737

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74394

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000674 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive sclerosing poliodystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Oct 01, 2018	The NM_002693.2:c.1950-9T>C (NP_002684.1:p.=) [GRCH38: NC_000015.10:g.89324236A>G] variant in POLG gene is interpretated to be a Likely Benign based on ACMG guidelines (PMID: 25741868). This variant meets the following evidence codes reported in the ACMG-guideline. BP4:Computational evidence/predictors indicate no impact on the POLG structure, function, or protein-protein interaction. BP6:Reputable source(s) without shared data suggest the variant is benign. Based on the evidence criteria codes applied, the variant is suggested to be Likely Benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 30, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	22
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.11		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: rs780378329; hg19: chr15-89867467;