rs3087379

Variant names:

• chr15-89333085-C-A
• rs3087379
• NM_002693.3:c.659+11G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-89333085-C-A
• chr15-89333085-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002693.3(POLG):​c.659+11G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000219 in 1,510,744 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (4 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.175
• Publications: 0 publications found

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:56246): (POLG alternative reading frame) This gene uses the same transcript as the POLG gene but has a CUG start codon and an alternate reading frame that makes a 260 aa protein. This protein is distinct from POLG isoforms and may interact with P32 (also known as C1QBP), a mitochondrial matrix protein thought to be involved in the expression of mitochondrial genome-encoded proteins. POLGARF protein may bind P32 and sequester it in the nucleolus. Interestingly, some disease-causing mutations thought to be in POLG may instead be associated with POLGARF. [provided by RefSeq, May 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-89333085-C-A is Benign according to our data. Variant chr15-89333085-C-A is described in ClinVar as Benign. ClinVar VariationId is 206494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002693.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.659+11G>T		intron	N/A	NP_002684.1
	POLGARF	NM_001430120.1	MANE Select	c.714+11G>T		intron	N/A	NP_001417049.1
	POLG	NM_001126131.2		c.659+11G>T		intron	N/A	NP_001119603.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.659+11G>T		intron	N/A	ENSP00000268124.5
	POLGARF	ENST00000706918.1	MANE Select	c.714+11G>T		intron	N/A	ENSP00000516626.1
	POLG	ENST00000442287.6	TSL:1	c.659+11G>T		intron	N/A	ENSP00000399851.2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152222 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000352 AC: 59 AN: 167486 AF XY: 0.000346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000230 AC: 312 AN: 1358404 Hom.: 4 Cov.: 31 AF XY: 0.000292 AC XY: 194 AN XY: 663940

African (AFR) AF: 0.0000333 AC: 1 AN: 29992

American (AMR) AF: 0.00 AC: 0 AN: 28790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19812

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38468

South Asian (SAS) AF: 0.00397 AC: 278 AN: 69944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48384

Middle Eastern (MID) AF: 0.000189 AC: 1 AN: 5284

European-Non Finnish (NFE) AF: 0.0000160 AC: 17 AN: 1061850

Other (OTH) AF: 0.000251 AC: 14 AN: 55880

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152340 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.4
DANN	Benign	0.84
PhyloP100		-0.17
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs3087379; hg19: chr15-89876316;