rs747253294

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_018062.4(FANCL):c.1007_1009del(p.Ile336_Cys337delinsSer) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,594,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

FANCL
NM_018062.4 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:5

Conservation

PhyloP100: 8.61

Variant links:

Genes affected

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

FANCL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_018062.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 2-58161532-CATA-C is Pathogenic according to our data. Variant chr2-58161532-CATA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241247.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=7, Pathogenic=1, Uncertain_significance=4}. Variant chr2-58161532-CATA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCL	NM_018062.4 linkuse as main transcript	c.1007_1009del	p.Ile336_Cys337delinsSer	inframe_deletion	12/14	ENST00000233741.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCL	ENST00000233741.9 linkuse as main transcript	c.1007_1009del	p.Ile336_Cys337delinsSer	inframe_deletion	12/14	1	NM_018062.4	P4	Q9NW38-1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000307

AC:

AN:

250564

Hom.:

AF XY:

0.000325

AC XY:

AN XY:

135454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000566

AC:

817

AN:

1443078

Hom.:

AF XY:

0.000555

AC XY:

399

AN XY:

719070

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.0000896

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000679

Gnomad4 OTH exome

AF:

0.00100

GnomAD4 genome

AF:

0.000329

AC:

AN:

151846

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74158

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000604

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000695

Hom.:

Bravo

AF:

0.000298

EpiCase

AF:

0.000873

EpiControl

AF:

0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group L

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 2018	The FANCL c.1022_1024delTAT (p.Ile341_Cys342delinsSer) variant is an in-frame deletion variant that results in the loss of isoleucine 341 and conversion of cysteine 342 to serine. It has been reported in a compound heterozygous state in two individuals with Fanconi anemia (FA) complementation group L (Ali et al. 2009; Chandrasekharappa et al. 2013) as well as in a cell line derived from an FA patient for whom no additional phenotypic details were available (Raghunandan et al. 2015). The variant was also identified in a heterozygous state in two individuals: a female with breast or ovarian cancer who came from a high-risk family and met guidelines for hereditary cancer risk evaluation (Maxwell et al. 2016) and a 12-year-old boy with bone marrow failure and short telomeres but no congenital anomalies (Zhang et al. 2015). Collet et al. (2015) identified the p.Ile341_Cys342delinsSer variant in one of 71 non-cancer control individuals, and the variant is reported at a frequency of 0.000627 in the European American population of the Genome Aggregation Database. Expression of the variant protein in a cell line lacking the FANCL protein was unable to rescue the phenotype of G2/M arrest, absent mono-ubiquitination with FANCD2, increased sensitivity to mitomycin C and a high rate of chromosome breakage, suggesting the variant impairs protein function (Ali et al. 2009).Based on the collective evidence, the p.Ile341_Cys342delinsServariant is classified as likely pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 25, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 01, 2021	FANCL NM_018062.3 exon 12 p.Ile336_Cys337delinsSer (c.1007_1009del): This variant has been reported in the literature in the compound heterozygous state in 2 individuals diagnosed with Fanconi anemi (FA), including one in trans with a pathogenic variant (Ali 2009 PMID:19405097; Chandrasekharappa 2013 PMID:23613520). Of note, one individual did not have clinical features typical of FA (Ali 2009 PMID:19405097). This variant has also been reported in the heterozygous state in an individual with bone marrow failure and short telomeres (Zhang 2015 PMID:25239263). This variant is present in 0.06% (41/67840) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-58161532-CATA-C?dataset=gnomad_r3). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with classifications ranging from Uncertain significance to pathogenic (Variation ID:241247). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein (Ali 2009 PMID:19405097). However, these studies may not accurately represent in vivo biological function. This variant represents an in-frame deletion, with 2 amino acids at positions 336 (Isoleucine) and 337 (Cysteine) removed and replaced by a Serine, and is not predicted to alter the reading frame. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2023	Has been reported previously as compound heterozygous with a frameshift variant in a child who was diagnosed with Fanconi anemia on the basis of a complementation assay who presented with slow growth, poor feeding, irritability, mildly delayed myelination on MRI, ADHD, a single cafe-au-lait spot, mild hypocellularity, and a family history of leukemia but no other features associated with Fanconi anemia (Ali et al., 2009); Has also been observed previously as compound heterozygous with a deep intronic variant which was prediced to result in abberant splicing in a sample from the International Fanconi anemia registry (Chandrasekharappa et al., 2013); Published functional studies demonstrate a damaging effect: studies in EUFA868 cells showed this allele resulted in substantial G2/M arrest, lack of FANCD2 monoubiquitination, increased sensitivity to mitomycin C, and a high rate of chromosome breakage (Ali et al., 2009); In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 2 amino acids and insertion of 1 incorrect amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 25659033, 19405097, 23613520, 34308104, 28104920, 31980526, 27153395, 25239263) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2021	- -

Fanconi anemia

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	This variant, c.1007_1009del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the FANCL protein (p.Ile336_Cys337delinsSer). This variant is present in population databases (rs747253294, gnomAD 0.06%). This variant has been observed in individual(s) with Fanconi anemia and/or osteosarcoma, Fanconi anemia and bone marrow failure syndromes (PMID: 19405097, 23613520, 28104920, 32191290, 34308104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 241247). 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 variant affects FANCL function (PMID: 19405097). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 04, 2019	The p.Ile341_Cys342delinsSer variant in FANCL has been reported in the compound heterozygous state in 2 individuals with Fanconi anemia (Ali 2009, Chandrasekhar appa 2013). It has also been identified in 0.06% (80/128464) of European chromos omes by gnomAD (http://gnomad.broadinstitute.org). This variant results in a del etion of 3 base pairs that results in the removal of 2 amino acids and introduct ion of a serine (Ser) at position 341 and is not predicted to alter the protein reading-frame. In vitro functional studies, including a complementation assay, s upport an impact on protein function (Ali 2009). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Fa nconi anemia. ACMG/AMP Criteria applied: PM3, PS3_Moderate, PM2_Supporting, PM4_ Supporting. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: FANCL c.1007_1009delTAT (p.Ile336_Cys337delinsSer) results in an in-frame deletion that is predicted to delete an isoleucine and cysteine and replace with a serine. The variant allele was found at a frequency of 0.00031 in 250564 control chromosomes (gnomAD), predominantly at a frequency of 0.00062 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCL causing Fanconi Anemia (0.00028), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1007_1009delTAT has been reported in the literature as a biallelic genotype in individuals affected with Fanconi Anemia (e.g. Ali_2009, Chandrasekharappa_2013, Raghunandan_2015). The variant was also found in the heterozygous state in individuals affected with breast/ovarian cancer (Maxwell_2016) and bone marrow failure (Guidugli_2017). These data indicate that the variant may be associated with disease. A complementation assay using a FANCL deficient cell line showed that when the variant was overexpressed in this deficient cell line, there was no recovery of FANCL activity, indicating a total loss of function (Ali_2009). The following publications have been ascertained in the context of this evaluation (PMID: 23613520, 27153395, 31980526, 19405097, 28104920, 25659033). Ten ClinVar submitters have assessed the variant since 2014 and classified as pathogenic/likely pathogenic (n=7) and VUS (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

FANCL-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2024

The FANCL c.1022_1024delTAT variant is predicted to result in an in-frame deletion (p.Ile341_Cys342delinsSer). This variant, also known as c.1007_1009del (p.Ile336_Cys337delinsSer), has been reported in the compound heterozygous state in two individuals with Fanconi anemia (Ali et al. 2009. PubMed ID: 19405097; Chandrasekharappa et al. 2013. PubMed ID: 23613520). This variant was also documented in the heterozygous state in individuals with bone marrow failure or a personal history of breast or ovarian cancer (Table S5, Zhang et al. 2015. PubMed ID: 25239263; Tables S4 & S5, Maxwell et al. 2016. PubMed ID: 27153395; Guidugli et al. 2017. PubMed ID: 28104920). Functional studies suggest that this variant alters cellular function (Ali et al. 2009. PubMed ID: 19405097). This variant is listed in ClinVar with varying interpretations ranging from Pathogenic (2), Likely Pathogenic (7), and Uncertain (4) (https://www.ncbi.nlm.nih.gov/clinvar/variation/241247/). This variant is reported in 0.062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. While we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Premature ovarian insufficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Jan 10, 2018

- -

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