rs9806604

Positions:

• chr15-89283265-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001113378.2(FANCI):​c.1698+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,612,664 control chromosomes in the GnomAD database, including 133,753 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (17029 hom., cov: 32)
  • Exomes 𝑓: 0.40 (116724 hom.)
• Consequence: FANCI NM_001113378.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.834

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 15-89283265-C-T is Benign according to our data. Variant chr15-89283265-C-T is described in ClinVar as [Benign]. Clinvar id is 257481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCI	NM_001113378.2	c.1698+15C>T		intron_variant		ENST00000310775.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCI	ENST00000310775.12	c.1698+15C>T		intron_variant		1	NM_001113378.2	P1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70053 AN: 151920 Hom.: 17005 Cov.: 32

Gnomad AFR AF: 0.623

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.492

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.433

GnomAD3 exomes AF: 0.412 AC: 103562 AN: 251368 Hom.: 22031 AF XY: 0.410 AC XY: 55642 AN XY: 135870

Gnomad AFR exome AF: 0.622

Gnomad AMR exome AF: 0.402

Gnomad ASJ exome AF: 0.375

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.402

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.397 AC: 579169 AN: 1460624 Hom.: 116724 Cov.: 34 AF XY: 0.396 AC XY: 288026 AN XY: 726666

Gnomad4 AFR exome AF: 0.630

Gnomad4 AMR exome AF: 0.399

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.404

Gnomad4 FIN exome AF: 0.479

Gnomad4 NFE exome AF: 0.387

Gnomad4 OTH exome AF: 0.409

GnomAD4 genome AF: 0.461 AC: 70117 AN: 152040 Hom.: 17029 Cov.: 32 AF XY: 0.465 AC XY: 34532 AN XY: 74316

Gnomad4 AFR AF: 0.623

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.492

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.430

Alfa AF: 0.429 Hom.: 2673

Bravo AF: 0.464

Asia WGS AF: 0.378 AC: 1312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group I Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs9806604; hg19: chr15-89826496; COSMIC: COSV55527271;