chr15-89317388-C-CG

Variant names:

• chr15-89317388-C-CG
• rs113994101
• NM_002693.3:c.3630dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

This summary comes from the ClinGen Evidence Repository: The c.3630dup (p.Gly1211ArgfsTer6) variant in POLG was not in any databases (PM2). This variant results in a frameshift causing a loss of function (PVS1). There are no publications of cases with this variant. In summary, this variant meets criteria to be classified as likely pathogenic for mitochondrial disease inherited in an autosomal recessive manner. ntDNA ACMG/AMP criteria for POLG applied: PVS1, PM2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA341888/MONDO:0044970/014

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLG NM_002693.3 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 O:1
• Conservation: PhyloP100: 0.164
• Publications: 2 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

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.3630dupC	p.Gly1211ArgfsTer6	frameshift	Exon 22 of 23	NP_002684.1
	POLG	NM_001126131.2		c.3630dupC	p.Gly1211ArgfsTer6	frameshift	Exon 22 of 23	NP_001119603.1
	FANCI	NM_018193.3		c.*929_*930insG		downstream_gene	N/A	NP_060663.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLG	ENST00000268124.11	TSL:1 MANE Select	c.3630dupC	p.Gly1211ArgfsTer6	frameshift	Exon 22 of 23	ENSP00000268124.5
	POLG	ENST00000442287.6	TSL:1	c.3630dupC	p.Gly1211ArgfsTer6	frameshift	Exon 22 of 23	ENSP00000399851.2
	POLG	ENST00000636937.2	TSL:5	c.3630dupC	p.Gly1211ArgfsTer6	frameshift	Exon 22 of 23	ENSP00000516154.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs113994101; hg19: chr15-89860619;