15-89316763-C-A

Variant names:

• chr15-89316763-C-A
• rs3087374
• NM_002693.3:c.3708G>T

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.3708G>T​(p.Gln1236His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0726 in 1,612,344 control chromosomes in the GnomAD database, including 5,095 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.061 (411 hom., cov: 32)
  • Exomes 𝑓: 0.074 (4684 hom.)
• Consequence: POLG NM_002693.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23 O:1
• Conservation: PhyloP100: 1.22
• Publications: 72 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]

FANCI (HGNC:25568): (FA complementation group I) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group I. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

FANCI Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group I

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for POLG are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014915764).
• BP6: Variant 15-89316763-C-A is Benign according to our data. Variant chr15-89316763-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 21316.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0825 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.3708G>T	p.Gln1236His	missense	Exon 23 of 23	NP_002684.1	P54098
	FANCI	NM_001113378.2	MANE Select	c.*304C>A		3_prime_UTR	Exon 38 of 38	NP_001106849.1	Q9NVI1-3
	POLG	NM_001126131.2		c.3708G>T	p.Gln1236His	missense	Exon 23 of 23	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.3708G>T	p.Gln1236His	missense	Exon 23 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3708G>T	p.Gln1236His	missense	Exon 23 of 23	ENSP00000399851.2	P54098
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.*304C>A		3_prime_UTR	Exon 38 of 38	ENSP00000310842.8	Q9NVI1-3

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 9240 AN: 152172 Hom.: 411 Cov.: 32

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0843

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0614 AC: 15410 AN: 250854 AF XY: 0.0623

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0495

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.0824

Gnomad OTH exome AF: 0.0668

GnomAD4 exome AF: 0.0738 AC: 107789 AN: 1460054 Hom.: 4684 Cov.: 30 AF XY: 0.0725 AC XY: 52697 AN XY: 726478

African (AFR) AF: 0.0126 AC: 423 AN: 33456

American (AMR) AF: 0.0359 AC: 1605 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0490 AC: 1279 AN: 26126

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39694

South Asian (SAS) AF: 0.0194 AC: 1673 AN: 86242

European-Finnish (FIN) AF: 0.142 AC: 7591 AN: 53412

Middle Eastern (MID) AF: 0.0851 AC: 490 AN: 5760

European-Non Finnish (NFE) AF: 0.0815 AC: 90443 AN: 1110304

Other (OTH) AF: 0.0709 AC: 4280 AN: 60338

GnomAD4 genome AF: 0.0606 AC: 9236 AN: 152290 Hom.: 411 Cov.: 32 AF XY: 0.0627 AC XY: 4672 AN XY: 74472

African (AFR) AF: 0.0148 AC: 614 AN: 41580

American (AMR) AF: 0.0457 AC: 699 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0182 AC: 88 AN: 4828

European-Finnish (FIN) AF: 0.160 AC: 1692 AN: 10600

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0843 AC: 5735 AN: 68012

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0710 Hom.: 2025

Bravo AF: 0.0515

TwinsUK AF: 0.0782 AC: 290

ALSPAC AF: 0.0742 AC: 286

ESP6500AA AF: 0.0175 AC: 77

ESP6500EA AF: 0.0811 AC: 697

ExAC AF: 0.0613 AC: 7447

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.0842

EpiControl AF: 0.0813

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (4)
-	-	2	Fanconi anemia complementation group I (2)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	POLG-Related Spectrum Disorders (1)
-	-	1	Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1 (1)
-	-	1	Progressive sclerosing poliodystrophy;C1834846:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 1;C1843851:Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis;C3150914:Mitochondrial DNA depletion syndrome 4b;C4225153:Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1;C4551995:Mitochondrial DNA depletion syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0015	T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.99	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.052	T
Polyphen		0.80	P
Vest4		0.098
MutPred		0.067		Loss of glycosylation at P1239 (P = 0.1381)
MPC		0.14
ClinPred		0.0096	T
GERP RS		5.0
PromoterAI		0.011	Neutral
Varity_R		0.16
gMVP		0.49
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3087374; hg19: chr15-89859994; COSMIC: COSV105090738;