rs1555536446
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_000135.4(FANCA):c.3520_3522delTGG(p.Trp1174del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000344 in 1,452,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
FANCA
NM_000135.4 conservative_inframe_deletion
NM_000135.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.53
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]
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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 16-89745062-GCCA-G is Pathogenic according to our data. Variant chr16-89745062-GCCA-G is described in ClinVar as [Pathogenic]. Clinvar id is 456115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89745062-GCCA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCA | NM_000135.4 | c.3520_3522delTGG | p.Trp1174del | conservative_inframe_deletion | 36/43 | ENST00000389301.8 | NP_000126.2 | |
| FANCA | NM_001286167.3 | c.3520_3522delTGG | p.Trp1174del | conservative_inframe_deletion | 36/43 | NP_001273096.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000344 AC: 5AN: 1452836Hom.: 0 AF XY: 0.00000415 AC XY: 3AN XY: 722720
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GnomAD4 genome
GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Oct 10, 2022 | This variant has been reported in the literature in the homozygous or compound heterozygous states in several individuals with Fanconi anemia (Selected publications: Levran 1997 PMID: 9371798; Chandrasekharappa 2013 PMID: 23613520; Donovan 2016 PMID: 26841305; Steinberg-Shemer 2020 PMID: 31558676). This variant is absent from large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic (Variation ID: 4561156). Functional studies have shown that this variant impacts the encoded protein's function (Adachi 2002 PMID: 12444097); however, these studies may not accurately represent in vivo biological function. This variant represents an in-frame deletion of 1 amino acid at position 1174 and is not predicted to alter the reading frame, but the effect of this variant on the protein is unclear. In summary, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
Fanconi anemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2023 | This variant, c.3520_3522del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Trp1174del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fanconi anemia (PMID: 9371789, 17924555, 23613520, 25703136). 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: 456115). 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 FANCA function (PMID: 12444097). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 02, 2023 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at