rs555449842
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000135.4(FANCA):c.1827-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000205 in 1,608,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
FANCA
NM_000135.4 splice_acceptor
NM_000135.4 splice_acceptor
Scores
3
3
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.72
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 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.7, offset of 2, new splice context is: tgttttcctgtgatccaaAGcag. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 16-89775816-C-T is Pathogenic according to our data. Variant chr16-89775816-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 408199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89775816-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.1827-1G>A | splice_acceptor_variant | ENST00000389301.8 | |||
FANCA | NM_001286167.3 | c.1827-1G>A | splice_acceptor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.1827-1G>A | splice_acceptor_variant | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152116Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246900Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133456
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GnomAD4 exome AF: 0.0000172 AC: 25AN: 1456292Hom.: 0 Cov.: 29 AF XY: 0.0000152 AC XY: 11AN XY: 724380
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74440
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 05, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | curation | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Feb 01, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | FANCA NM_000135 exon 21 c.1827-1G>A: This variant has been reported in the literature in 5 individuals with Fanconi Anemia as homozygous or compound heterozygous (Moghrabi 2009 PMID:19367192). This variant is present in 7/124746 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs555449842). This variant is present in ClinVar (Variation ID:408199). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Mathew 2006 PMID:16998502). In summary, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 06, 2021 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Sue Richards. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 10, 2021 | NM_000135.2(FANCA):c.1827-1G>A is a canonical splice variant classified as pathogenic in the context of Fanconi anemia complementation group A. c.1827-1G>A has been observed in cases with relevant disease (PMID: 19367192). Functional assessments of this variant are not available in the literature. c.1827-1G>A has been observed in population frequency databases (gnomAD NFE 0.005%). In summary, NM_000135.2(FANCA):c.1827-1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Fanconi anemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change affects an acceptor splice site in intron 20 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 present in population databases (rs555449842, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with Fanconi anemia (PMID: 19367192, 29098742). ClinVar contains an entry for this variant (Variation ID: 408199). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | Dec 07, 2022 | Variant summary: FANCA c.1827-1G>A 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: three predict the variant abolishes a 3' acceptor site, and two predict the variant strengthens a cryptic exonic 3' acceptor site, 5 nucleotides downstream from the original site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 246900 control chromosomes (gnomAD v2.1). c.1827-1G>A has been reported in the literature in multiple homozygous- and compound heterozygous individuals affected with Fanconi Anemia (e.g. Moghrabi_2009, Chandrasekharappa_2013, Kimble_2018, Adair_2018). 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. Six ClinVar submitters (evaluation after 2014) have all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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DS_AL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at