rs397507553
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000135.4(FANCA):c.3788_3790delTCT(p.Phe1263del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000102 in 1,613,544 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
FANCA
NM_000135.4 disruptive_inframe_deletion
NM_000135.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.09
Genes affected
FANCA (HGNC:3582): (FA complementation group A) 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 A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]
ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000135.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-89740841-GAGA-G is Pathogenic according to our data. Variant chr16-89740841-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 41003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Likely_pathogenic]. Variant chr16-89740841-GAGA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCA | NM_000135.4 | c.3788_3790delTCT | p.Phe1263del | disruptive_inframe_deletion | Exon 38 of 43 | ENST00000389301.8 | NP_000126.2 | |
| ZNF276 | NM_001113525.2 | c.*2603_*2605delGAA | 3_prime_UTR_variant | Exon 11 of 11 | ENST00000443381.7 | NP_001106997.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| FANCA | ENST00000389301.8 | c.3788_3790delTCT | p.Phe1263del | disruptive_inframe_deletion | Exon 38 of 43 | 1 | NM_000135.4 | ENSP00000373952.3 | ||
| ZNF276 | ENST00000443381.7 | c.*2603_*2605delGAA | 3_prime_UTR_variant | Exon 11 of 11 | 1 | NM_001113525.2 | ENSP00000415836.2 |
Frequencies
GnomAD3 genomes 0.0000920 AC: 14AN: 152092Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000997 AC: 25AN: 250632Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135502
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GnomAD4 exome AF: 0.000103 AC: 150AN: 1461334Hom.: 0 AF XY: 0.000105 AC XY: 76AN XY: 726922
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GnomAD4 genome 0.0000920 AC: 14AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74416
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 24, 2019 | NM_000135.2(FANCA):c.3788_3790delTCT(F1263del) is classified as pathogenic in the context of Fanconi anemia complementation group A. Sources cited for classification include the following: PMID 24584348, 17924555 and 19367192. Classification of NM_000135.2(FANCA):c.3788_3790delTCT(F1263del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter, Sue Richards. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | Sep 22, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 16, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 11, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | research | Human Genetics Section, Sidra Medicine | Jul 11, 2024 | Franklin and VarSome were utilized as supplementary tools to predict the pathogenicity of the identified variant. The patient exhibited the following symptoms: Skin: Café-au-lait spots Malformations: ischiopubic synchondroses asymmetry (normal variant) Head: Microcephaly Growth retardation: below 5th centile Consequently, Whole Genome Sequencing (WGS) was performed, which identified the variant responsible for the observed phenotypes. We are currently preparing the publication detailing these findings, and the PubMed ID (PMID) will be provided upon its release. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jan 31, 2023 | ACMG classification criteria: PS3 supporting, PM2 supporting, PM3 very strong, PM4 - |
Fanconi anemia Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Dec 08, 2017 | This inframe deletion of a single amino acid has been reported as a homozygous and compound heterozygous change in individuals with Fanconi Anemia from ethnically diverse populations (PMID: 9371798, 21273304, 20301575). The highest allele frequency in the ExAC and gnomAD population databases is 0.03% with no reported homozygotes. Based on the available evidence, c.3788_3790delTCT (p. Phe1263del) is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Feb 01, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 06, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 24, 2024 | This variant, c.3788_3790del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Phe1263del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397507553, gnomAD 0.02%). This variant has been observed in individual(s) with Fanconi anemia (FA) (PMID: 9371798, 15643609, 21273304, 21659346). It has also been observed to segregate with disease in related individuals. 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 variant affects FANCA function (PMID: 21273304). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2022 | Variant summary: FANCA c.3788_3790delTCT (p.Phe1263del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 0.0001 in 250632 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in FANCA causing Fanconi Anemia (0.0001 vs 0.0022), allowing no conclusion about variant significance. c.3788_3790delTCT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Fanconi Anemia (e.g. Castella_2011, Pilonetto_2017). These data indicate that the variant is very likely to be associated with disease. Eleven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | FANCA: PM3:Strong, PM2, PM4, PS3:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 03, 2022 | The frequency of this variant in the general population, 0.00017 (6/35374 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in the homozygous or compound heterozygous state in many individuals with Fanconi anemia (PMIDs: 28717661 (2017), 24584348 (2014), 22778927 (2012), 21273304 (2011), 21659346 (2011), 19367192 (2009), 17924555 (2008), 10094191 (1999), 9371798 (1997)), and in individuals with hereditary breast cancer (PMID: 32235514 (2020)). This variant is thought to be the most common FANCA mutation in the world, and is present in many different ethnicities, especially Hispanic and Caucasian populations (PMID: 9371798 (1997)). In functional studies, this variant was shown to have a damaging effect on FANCA protein function and cellular interaction (PMIDs: 21273304 (2011), 12444097 (2002)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | Published functional studies demonstrate a damaging effect: Impaired FANCA phosphorylation, FANCD2 monoubiquitination, nuclear localization, and interaction with FANCC and FANCF (PMID: 12444097); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15643609, 21659346, 9371798, 24584348, 26740942, 21273304, 26556299, 29904161, 31030435, 28717661, 32235514, 31019026, 31980526, 31558676, 33960719, 33679882, 31589614, 33172906, 32793304, 33718801, 35295078, 34308104, 34958143, 30809872, 35988656, 36113475, 34645491, 36135330, 12444097) - |
FANCA-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2024 | The FANCA c.3788_3790delTCT variant is predicted to result in an in-frame deletion (p.Phe1263del). This variant has been reported in the homozygous or compound heterozygous state in many individuals with Fanconi anemia (Levran et al 1997. PubMed ID: 9371798; Castella et al 2011. PubMed ID: 21273304; Steinberg-Shemer et al. 2020. PubMed ID: 31558676; Thompson et al. 2021. PubMed ID: 33960719). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD, and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41003/). This variant is interpreted as pathogenic. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
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