rs2307438

Variant names:

• chr15-89317555-A-C
• rs2307438
• NM_002693.3:c.3483-19T>G

Your query was ambiguous. Multiple possible variants found:

• chr15-89317555-A-C
• chr15-89317555-A-T

Variant summary

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

The ENST00000268124.11(POLG):​c.3483-19T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,608,966 control chromosomes in the GnomAD database, including 132,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (14769 hom., cov: 31)
  • Exomes 𝑓: 0.40 (117806 hom.)
• Consequence: POLG ENST00000268124.11 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.383
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mitochondrial DNA depletion syndrome 4a

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, 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: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-89317555-A-C is Benign according to our data. Variant chr15-89317555-A-C is described in ClinVar as Benign. ClinVar VariationId is 138763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.513 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000268124.11. 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.3483-19T>G		intron	N/A	NP_002684.1
	POLG	NM_001126131.2		c.3483-19T>G		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.3483-19T>G		intron	N/A	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.3483-19T>G		intron	N/A	ENSP00000399851.2
	POLG	ENST00000526671.1	TSL:2	n.274T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66310 AN: 151604 Hom.: 14747 Cov.: 31

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.390

Gnomad AMR AF: 0.422

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.390

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.421 AC: 105528 AN: 250716 AF XY: 0.417

Gnomad AFR exome AF: 0.515

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.393

Gnomad EAS exome AF: 0.359

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.393

Gnomad OTH exome AF: 0.406

GnomAD4 exome AF: 0.399 AC: 581755 AN: 1457244 Hom.: 117806 Cov.: 33 AF XY: 0.399 AC XY: 289157 AN XY: 725206

African (AFR) AF: 0.520 AC: 17373 AN: 33378

American (AMR) AF: 0.488 AC: 21800 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 10301 AN: 26098

East Asian (EAS) AF: 0.339 AC: 13451 AN: 39684

South Asian (SAS) AF: 0.398 AC: 34272 AN: 86176

European-Finnish (FIN) AF: 0.471 AC: 24943 AN: 53006

Middle Eastern (MID) AF: 0.376 AC: 2168 AN: 5764

European-Non Finnish (NFE) AF: 0.391 AC: 432905 AN: 1108158

Other (OTH) AF: 0.407 AC: 24542 AN: 60266

GnomAD4 genome AF: 0.437 AC: 66376 AN: 151722 Hom.: 14769 Cov.: 31 AF XY: 0.443 AC XY: 32825 AN XY: 74138

African (AFR) AF: 0.518 AC: 21440 AN: 41352

American (AMR) AF: 0.421 AC: 6425 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.379 AC: 1314 AN: 3466

East Asian (EAS) AF: 0.354 AC: 1820 AN: 5136

South Asian (SAS) AF: 0.392 AC: 1879 AN: 4796

European-Finnish (FIN) AF: 0.485 AC: 5108 AN: 10528

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27064 AN: 67886

Other (OTH) AF: 0.409 AC: 864 AN: 2110

Alfa AF: 0.425 Hom.: 5323

Bravo AF: 0.440

Asia WGS AF: 0.376 AC: 1306 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Progressive sclerosing poliodystrophy (3)
-	-	2	not provided (2)
-	-	1	Mitochondrial DNA depletion syndrome 4b (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	-0.86
CADD	Benign	11
DANN	Benign	0.82
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2307438; hg19: chr15-89860786; COSMIC: COSV51521392; COSMIC: COSV51521392;