NM_002693.3:c.3597C>A

Variant names:

• chr15-89317422-G-T
• rs2307443
• NM_002693.3:c.3597C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002693.3(POLG):​c.3597C>A​(p.Thr1199Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,613,984 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T1199T) has been classified as Likely benign. The gene POLG is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0074 (3 hom., cov: 32)
  • Exomes 𝑓: 0.010 (115 hom.)
• Consequence: POLG NM_002693.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:15
• Conservation: PhyloP100: -0.700
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 15-89317422-G-T is Benign according to our data. Variant chr15-89317422-G-T is described in ClinVar as Benign. ClinVar VariationId is 138766.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-0.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00736 (1120/152204) while in subpopulation NFE AF = 0.0112 (759/68014). AF 95% confidence interval is 0.0105. There are 3 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	NM_002693.3	MANE Select	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	NP_002684.1	P54098
	POLG	NM_001126131.2		c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	NP_001119603.1	P54098
	FANCI	NM_018193.3		c.*963G>T		downstream_gene	N/A	NP_060663.2	Q9NVI1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000268124.5	P54098
	POLG	ENST00000442287.6	TSL:1	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000399851.2	P54098
	POLG	ENST00000636937.2	TSL:5	c.3597C>A	p.Thr1199Thr	synonymous	Exon 22 of 23	ENSP00000516154.1	P54098

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152086 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00788 AC: 1981 AN: 251490 AF XY: 0.00800

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.0104 AC: 15255 AN: 1461780 Hom.: 115 Cov.: 31 AF XY: 0.00998 AC XY: 7255 AN XY: 727202

African (AFR) AF: 0.00125 AC: 42 AN: 33478

American (AMR) AF: 0.00203 AC: 91 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 348 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00274 AC: 236 AN: 86258

European-Finnish (FIN) AF: 0.0119 AC: 638 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0120 AC: 13397 AN: 1111904

Other (OTH) AF: 0.00821 AC: 496 AN: 60394

GnomAD4 genome AF: 0.00736 AC: 1120 AN: 152204 Hom.: 3 Cov.: 32 AF XY: 0.00718 AC XY: 534 AN XY: 74416

African (AFR) AF: 0.00198 AC: 82 AN: 41508

American (AMR) AF: 0.00222 AC: 34 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4814

European-Finnish (FIN) AF: 0.0160 AC: 170 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0112 AC: 759 AN: 68014

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

Alfa AF: 0.00901 Hom.: 7

Bravo AF: 0.00614

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00900

EpiControl AF: 0.00978

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Progressive sclerosing poliodystrophy (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Mitochondrial disease (1)
-	-	1	POLG-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.0
DANN	Benign	0.77
PhyloP100		-0.70
Mutation Taster		=96/4	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

Other links and lift over

dbSNP: rs2307443; hg19: chr15-89860653;