chr16-89758701-CCTGCCTAGAACAGCAAACA-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000135.4(FANCA):c.2853-15_2856delTGTTTGCTGTTCTAGGCAG(p.Gln952fs) variant causes a frameshift, splice acceptor, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
FANCA
NM_000135.4 frameshift, splice_acceptor, splice_region, intron
NM_000135.4 frameshift, splice_acceptor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.63
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-89758701-CCTGCCTAGAACAGCAAACA-C is Pathogenic according to our data. Variant chr16-89758701-CCTGCCTAGAACAGCAAACA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89758701-CCTGCCTAGAACAGCAAACA-C is described in Lovd as [Pathogenic]. Variant chr16-89758701-CCTGCCTAGAACAGCAAACA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| FANCA | NM_000135.4 | c.2853-15_2856delTGTTTGCTGTTCTAGGCAG | p.Gln952fs | frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant | Exon 30 of 43 | ENST00000389301.8 | NP_000126.2 | |
| FANCA | NM_001286167.3 | c.2853-15_2856delTGTTTGCTGTTCTAGGCAG | p.Gln952fs | frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant | Exon 30 of 43 | NP_001273096.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion, Medical Genetics | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000550055 / PMID: 9371798). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 19, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 05, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 13, 2024 | - - |
| 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. - |
Fanconi anemia Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2023 | This variant results in the deletion of part of exon 30 (c.2853-15_2856del) of the FANCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Fanconi anemia (PMID: 9371798, 17924555, 28717661). This variant is also known as c.2853-19del19 or IVS29(-19)-1del. ClinVar contains an entry for this variant (Variation ID: 550055). 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 | Aug 08, 2022 | Variant summary: FANCA c.2853-15_2856del19 is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant was absent in 251182 control chromosomes. c.2853-15_2856del19 has been reported in the literature in multiple individuals affected with Fanconi Anemia (eg. Levran_1997, Levran_2005, Pilonetto_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 02, 2024 | The FANCA c.2853-15_2856del variant disrupts a canonical splice-acceptor site and interferes with normal FANCA mRNA splicing. This variant has been reported in the published literature in individuals with Fanconi anemia (PMIDs: 28717661 (2017), 17924555 (2008), 9371798 (1997)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at