rs587778340

chr11-22625325-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_022725.4(FANCF):c.484_485del(p.Leu162AspfsTer103) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: FANCF NM_022725.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 0.977

Genes affected

FANCF (HGNC:3587): (FA complementation group F) 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 F. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-22625325-CAG-C is Pathogenic according to our data. Variant chr11-22625325-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 6343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-22625325-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCF	NM_022725.4	c.484_485del	p.Leu162AspfsTer103	frameshift_variant	1/1	ENST00000327470.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCF	ENST00000327470.6	c.484_485del	p.Leu162AspfsTer103	frameshift_variant	1/1		NM_022725.4	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152256 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000759 AC: 19 AN: 250260 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135758

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000163 AC: 238 AN: 1461880 Hom.: 0 AF XY: 0.000162 AC XY: 118 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000192

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152256 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74380

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group F Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 01, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The FANCF c.484_485delCT (p.Leu162AspfsTer103) variant results in a frameshift, and is predicted to cause premature termination of the protein. The p.Leu162AspfsTer103 variant has been reported in three studies in which it is found in a total of six patients with Fanconi anemia including in four in homozygous state (including three sibling fetuses terminated for congenital anomalies), and in two in a compound heterozygous state (de Winter et al. 2000; Nicchia et al. 2015; Chandra et al. 2005). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the South Asian population of the Exome Aggregation Consortium. The FANCF protein was absent in lymphoblasts from an individual who was homozygous for the variant (de Winter et al. 2000). Due to the potential impact of frameshift variants and the collective evidence, the p.Leu162AspfsTer103 variant is classified as pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Fanconi anemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2023	This sequence change creates a premature translational stop signal (p.Leu162Aspfs*103) in the FANCF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 213 amino acid(s) of the FANCF protein. This variant is present in population databases (rs587778340, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Fanconi anemia (FA) (PMID: 26033879, 27714961, 28102861). ClinVar contains an entry for this variant (Variation ID: 6343). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FANCF function (PMID: 10615118). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2019

Observed with a second FANCF variant in multiple individuals with Fanconi anemia (Tryon et al., 2017); Published functional studies demonstrate a damaging effect by disrupt protein expression (de Winter et al., 2000); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 213 amino acids are lost and replaced with 102 incorrect amino acids Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31589614, 26689913, 27714961, 10615118, 28687971, 28102861, 16084127, 26033879) -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

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: rs587778340; hg19: chr11-22646871;