chr15-89319113-AAC-A

Variant names:

• chr15-89319113-AAC-A
• rs146915033
• NM_002693.3:c.3105-16_3105-15delGT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002693.3(POLG):​c.3105-16_3105-15delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,614,204 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.478

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]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-89319113-AAC-A is Benign according to our data. Variant chr15-89319113-AAC-A is described in ClinVar as [Benign]. Clinvar id is 206472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-89319113-AAC-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00364 (555/152320) while in subpopulation AFR AF = 0.0128 (534/41576). AF 95% confidence interval is 0.0119. There are 5 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLG	NM_002693.3	c.3105-16_3105-15delGT		intron_variant	Intron 19 of 22	ENST00000268124.11	NP_002684.1
POLG	NM_001126131.2	c.3105-16_3105-15delGT		intron_variant	Intron 19 of 22		NP_001119603.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLG	ENST00000268124.11	c.3105-16_3105-15delGT		intron_variant	Intron 19 of 22	1	NM_002693.3	ENSP00000268124.5

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152202 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

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: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000978 AC: 246 AN: 251468 AF XY: 0.000670

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000415 AC: 606 AN: 1461884 Hom.: 6 AF XY: 0.000358 AC XY: 260 AN XY: 727244

Gnomad4 AFR exome AF: 0.0149 AC: 499 AN: 33480

Gnomad4 AMR exome AF: 0.000738 AC: 33 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.0000232 AC: 2 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.0000171 AC: 19 AN: 1112002

Gnomad4 Remaining exome AF: 0.000811 AC: 49 AN: 60396

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152320 Hom.: 5 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74496

Gnomad4 AFR AF: 0.0128 AC: 0.0128439 AN: 0.0128439

Gnomad4 AMR AF: 0.000914 AC: 0.000914435 AN: 0.000914435

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147016 AN: 0.0000147016

Gnomad4 OTH AF: 0.00284 AC: 0.00283822 AN: 0.00283822

Alfa AF: 0.00177 Hom.: 0

Bravo AF: 0.00440

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Apr 15, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 16, 2013

GeneDx

Significance: Benign

Review Status: flagged submission

Collection Method: clinical testing

The variant is found in EPILEPSY,INFANT-EPI,CHILD-EPI panel(s). -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive sclerosing poliodystrophy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs146915033; hg19: chr15-89862344;