rs71464462

Positions:

• chr15-89314480-A-ATACAAG

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCI	NM_001113378.2	c.3721-127_3721-126insGTACAA		intron_variant		ENST00000310775.12	NP_001106849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCI	ENST00000310775.12	c.3721-127_3721-126insGTACAA		intron_variant		1	NM_001113378.2	ENSP00000310842	P1

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

Gnomad4 AFR exome AF: 0.791

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.487

Gnomad4 EAS exome AF: 0.406

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.524

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.487

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

Gnomad4 AFR AF: 0.794

Gnomad4 AMR AF: 0.463

Gnomad4 ASJ AF: 0.478

Gnomad4 EAS AF: 0.433

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.536

Gnomad4 NFE AF: 0.468

Gnomad4 OTH AF: 0.522

Alfa AF: 0.548 Hom.: 2543

Bravo AF: 0.571

Asia WGS AF: 0.470 AC: 1633 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 29, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs55725136; hg19: chr15-89857711;