chr15-89319135-T-C

Variant names:

• chr15-89319135-T-C
• rs2246900
• NM_002693.3:c.3105-36A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002693.3(POLG):​c.3105-36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.378 in 1,613,776 control chromosomes in the GnomAD database, including 118,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.32 (8995 hom., cov: 33)
  • Exomes 𝑓: 0.38 (109213 hom.)
• Consequence: POLG NM_002693.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.442
• Publications: 20 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]

POLG Gene-Disease associations (from GenCC):

• progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• mitochondrial DNA depletion syndrome 4a

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sensory ataxic neuropathy, dysarthria, and ophthalmoparesis

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• autosomal dominant progressive external ophthalmoplegia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive progressive external ophthalmoplegia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial neurogastrointestinal encephalomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive mitochondrial ataxia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia with epilepsy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-89319135-T-C is Benign according to our data. Variant chr15-89319135-T-C is described in ClinVar as Benign. ClinVar VariationId is 619492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.3105-36A>G		intron	N/A	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3105-36A>G		intron	N/A	NP_001119603.1	P54098

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.3105-36A>G		intron	N/A	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3105-36A>G		intron	N/A	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.3105-36A>G		intron	N/A	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49225 AN: 152008 Hom.: 8993 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.325

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.374 AC: 94018 AN: 251406 AF XY: 0.381

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.326

Gnomad FIN exome AF: 0.476

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.383 AC: 559976 AN: 1461650 Hom.: 109213 Cov.: 41 AF XY: 0.385 AC XY: 279617 AN XY: 727154

African (AFR) AF: 0.140 AC: 4675 AN: 33480

American (AMR) AF: 0.365 AC: 16330 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 10060 AN: 26134

East Asian (EAS) AF: 0.312 AC: 12388 AN: 39696

South Asian (SAS) AF: 0.398 AC: 34326 AN: 86252

European-Finnish (FIN) AF: 0.468 AC: 25021 AN: 53416

Middle Eastern (MID) AF: 0.340 AC: 1962 AN: 5768

European-Non Finnish (NFE) AF: 0.389 AC: 432551 AN: 1111792

Other (OTH) AF: 0.375 AC: 22663 AN: 60390

GnomAD4 genome AF: 0.324 AC: 49230 AN: 152126 Hom.: 8995 Cov.: 33 AF XY: 0.332 AC XY: 24671 AN XY: 74368

African (AFR) AF: 0.152 AC: 6309 AN: 41518

American (AMR) AF: 0.328 AC: 5010 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1288 AN: 3472

East Asian (EAS) AF: 0.326 AC: 1681 AN: 5164

South Asian (SAS) AF: 0.391 AC: 1888 AN: 4826

European-Finnish (FIN) AF: 0.483 AC: 5112 AN: 10580

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26829 AN: 67966

Other (OTH) AF: 0.316 AC: 667 AN: 2110

Alfa AF: 0.354 Hom.: 2669

Bravo AF: 0.307

Asia WGS AF: 0.333 AC: 1155 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Progressive sclerosing poliodystrophy (3)
-	-	2	not provided (2)
-	-	1	Mitochondrial DNA depletion syndrome 4b (1)
-	-	1	not specified (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 (1)
-	-	1	Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.71
PhyloP100		0.44
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2246900; hg19: chr15-89862366; COSMIC: COSV51521755; COSMIC: COSV51521755;