rs587778340

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_022725.4(FANCF):c.484_485delCT(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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:1

Conservation

PhyloP100: 0.977

Variant links:

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]

FANCF links:

GAS2 (HGNC:4167): (growth arrest specific 2) The protein encoded by this gene is a caspase-3 substrate that plays a role in regulating microfilament and cell shape changes during apoptosis. It can also modulate cell susceptibility to p53-dependent apoptosis by inhibiting calpain activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2017]

GAS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Fraction of 0.57 CDS is truncated, and there are 3 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 rank	MANE	Protein	UniProt
FANCF	NM_022725.4 link	c.484_485delCT	p.Leu162AspfsTer103	frameshift_variant	Exon 1 of 1	ENST00000327470.6	NP_073562.1	Q9NPI8A3KME0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCF	ENST00000327470.6 link	c.484_485delCT	p.Leu162AspfsTer103	frameshift_variant	Exon 1 of 1	6	NM_022725.4	ENSP00000330875.3		Q9NPI8
GAS2	ENST00000648096.1 link	n.-183_-182delAG		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

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:

AN:

250260

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135758

show subpopulations

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.:

AF XY:

0.000162

AC XY:

118

AN XY:

727240

show subpopulations

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:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74380

show subpopulations

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.:

Bravo

AF:

0.0000793

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group F

Pathogenic:5

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FANCF c.484_485del; p.Leu162AspfsTer103 (rs587778340) is reported in the literature in the compound heterozygous and homozygous states in at least nine individuals (including three siblings) affected with Fanconi anemia (Chandra 2005, Chandrasekharappa 2013, Muramatsu 2017, Nicchia 2015, Tryon 2017). This variant is also reported in ClinVar (Variation ID: 6343). This variant is found in the non-Finnish European population with an allele frequency of 0.01% (14/128732) alleles) in the Genome Aggregation Database (v2.1.1). In vitro functional analyses demonstrate this mutant results in absent FANCF protein (de Winter 2000). This variant results in a premature termination codon in a single-exon gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated FANCF protein that would include a sequence of 102 amino acid residues not usually present. Based on available information, this variant is considered to be pathogenic. References: Chandra S et al. A rapid method for retrovirus-mediated identification of complementation groups in Fanconi anemia patients. Mol Ther. 2005 Nov. PMID: 16084127. Chandrasekharappa SC et al. Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Blood. 2013 May 30. PMID: 23613520. de Winter JP et al. The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM. Nature genetics. 2000 Jan. PMID: 10615118. Muramatsu H et al. Clinical utility of next-generation sequencing for inherited bone marrow failure syndromes. Genet Med. 2017 Jul. PMID: 28102861. Nicchia E et al. Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing. Birth Defects Res A Clin Mol Teratol. 2015 Dec. PMID: 26033879. Tryon R et al. Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations. Am J Med Genet A. 2017 Jan. PMID: 27714961. -

Mar 20, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Fanconi anemia

Pathogenic:3

Sep 17, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 gene product 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. -

Jan 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FANCF c.484_485delCT (p.Leu162AspfsX103) results in a premature termination codon, predicted to cause a truncation of the encoded protein but not expected to result in nonsense mediated decay. The variant allele was found at a frequency of 7.6e-05 in 250260 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCF causing Fanconi Anemia (7.6e-05 vs 0.0004), allowing no conclusion about variant significance. c.484_485delCT has been reported in the literature in multiple individuals affected with Fanconi Anemia (example: Chandrasekharappa_2013, Wang_2023, Nicchia _2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23613520, 36513378, 26033879). ClinVar contains an entry for this variant (Variation ID: 6343). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Aug 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported with a second FANCF variant in multiple individuals with Fanconi anemia (PMID: 27714961); Published functional studies demonstrate disruption of protein expression (PMID: 10615118); Frameshift variant predicted to result in abnormal protein length as the last 213 amino acids are replaced with 102 different amino acids, and other similar variants have been reported in HGMD; This variant is associated with the following publications: (PMID: 16084127, 28102861, 10615118, 28687971, 26689913, 34426522, 31589614, 34117267, 34308104, 36200007, 26033879, 27714961) -

FANCF-related disorder

Pathogenic:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCF c.484_485delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu162Aspfs*103). This variant has been reported as a cause of Fanconi anemia in several patients (de Winter et al. 2000. PubMed ID: 10615118; Tryon et al. 2016. PubMed ID: 27714961; Muramatsu et al. 2017. PubMed ID: 28102861; https://databases.lovd.nl/shared/variants/FANCF/). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD. This variant is classified as pathogenic by multiple submitters in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/6343/). Frameshift variants in FANCF are expected to be pathogenic. This variant is interpreted as pathogenic. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over