NM_001113378.2:c.3721-127_3721-126insGTACAA

Variant names:

• chr15-89314480-A-ATACAAG
• rs55725136
• NM_001113378.2:c.3721-127_3721-126insGTACAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001113378.2(FANCI):​c.3721-127_3721-126insGTACAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 715,252 control chromosomes in the GnomAD database, including 89,979 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (25547 hom., cov: 0)
  • Exomes 𝑓: 0.47 (64432 hom.)
• Consequence: FANCI NM_001113378.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176
• Publications: 2 publications found

Genes affected

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]

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 -16 ACMG points.

• BP6: Variant 15-89314480-A-ATACAAG is Benign according to our data. Variant chr15-89314480-A-ATACAAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001113378.2. 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
	FANCI	NM_001113378.2	MANE Select	c.3721-127_3721-126insGTACAA		intron	N/A	NP_001106849.1	Q9NVI1-3
	FANCI	NM_001376911.1		c.3721-127_3721-126insGTACAA		intron	N/A	NP_001363840.1	Q9NVI1-3
	FANCI	NM_018193.3		c.3541-127_3541-126insGTACAA		intron	N/A	NP_060663.2	Q9NVI1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCI	ENST00000310775.12	TSL:1 MANE Select	c.3721-132_3721-131insTACAAG		intron	N/A	ENSP00000310842.8	Q9NVI1-3
	FANCI	ENST00000674831.1		c.3853-132_3853-131insTACAAG		intron	N/A	ENSP00000502474.1	A0A6Q8PH09
	FANCI	ENST00000940814.1		c.3745-132_3745-131insTACAAG		intron	N/A	ENSP00000610873.1

Frequencies

GnomAD3 genomes AF: 0.561 AC: 84996 AN: 151436 Hom.: 25501 Cov.: 0

Gnomad AFR AF: 0.794

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.526

GnomAD4 exome AF: 0.472 AC: 266181 AN: 563696 Hom.: 64432 AF XY: 0.471 AC XY: 142793 AN XY: 303152

African (AFR) AF: 0.791 AC: 11888 AN: 15024

American (AMR) AF: 0.444 AC: 14231 AN: 32074

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 9089 AN: 18682

East Asian (EAS) AF: 0.406 AC: 13035 AN: 32124

South Asian (SAS) AF: 0.475 AC: 27919 AN: 58834

European-Finnish (FIN) AF: 0.524 AC: 18907 AN: 36098

Middle Eastern (MID) AF: 0.480 AC: 1914 AN: 3990

European-Non Finnish (NFE) AF: 0.459 AC: 154292 AN: 336264

Other (OTH) AF: 0.487 AC: 14906 AN: 30606

GnomAD4 genome AF: 0.561 AC: 85084 AN: 151556 Hom.: 25547 Cov.: 0 AF XY: 0.563 AC XY: 41641 AN XY: 74026

African (AFR) AF: 0.794 AC: 32762 AN: 41252

American (AMR) AF: 0.463 AC: 7055 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1658 AN: 3468

East Asian (EAS) AF: 0.433 AC: 2233 AN: 5152

South Asian (SAS) AF: 0.479 AC: 2306 AN: 4816

European-Finnish (FIN) AF: 0.536 AC: 5625 AN: 10504

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.468 AC: 31729 AN: 67808

Other (OTH) AF: 0.522 AC: 1101 AN: 2110

Alfa AF: 0.548 Hom.: 2543

Bravo AF: 0.571

Asia WGS AF: 0.470 AC: 1633 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs55725136; hg19: chr15-89857711;