16-89803284-GTTC-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000135.4(FANCA):c.764_766delGAA(p.Arg255del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
FANCA
NM_000135.4 disruptive_inframe_deletion
NM_000135.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.893
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 Uncertain_significance. Variant got 3 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.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCA | NM_000135.4 | c.764_766delGAA | p.Arg255del | disruptive_inframe_deletion | 8/43 | ENST00000389301.8 | NP_000126.2 | |
| FANCA | NM_001286167.3 | c.764_766delGAA | p.Arg255del | disruptive_inframe_deletion | 8/43 | NP_001273096.1 | ||
| FANCA | NM_001018112.3 | c.764_766delGAA | p.Arg255del | disruptive_inframe_deletion | 8/11 | NP_001018122.1 | ||
| FANCA | NM_001351830.2 | c.668_670delGAA | p.Arg223del | disruptive_inframe_deletion | 7/10 | NP_001338759.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.000145 AC: 22AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251420Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135906
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461788Hom.: 0 AF XY: 0.0000371 AC XY: 27AN XY: 727200
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GnomAD4 genome 0.000144 AC: 22AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74472
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia Uncertain:2
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 26, 2022 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 23, 2022 | This variant, c.764_766del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Arg255del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs555210441, gnomAD 0.02%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 9371798). ClinVar contains an entry for this variant (Variation ID: 134292). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Fanconi anemia complementation group A Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 31, 2019 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 18, 2024 | The FANCA c.764_766del (p.Arg255del) variant has been reported in the published literature in individual(s) with Fanconi anemia (PMID: 9371798 (1997)) as well as in reportedly healthy individuals (PMID: 24728327 (2014), 29641532 (2018)). The frequency of this variant in the general population, 0.00028 (7/24964 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 13, 2022 | PM4 - |
FANCA-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2024 | The FANCA c.764_766delGAA variant is predicted to result in an in-frame deletion (p.Arg255del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
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Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at