rs786204246
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Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000135.4(FANCA):βc.3403_3405delβ(p.Phe1135del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000212 in 1,413,240 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
FANCA
NM_000135.4 inframe_deletion
NM_000135.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.43
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 13 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 12 uncertain in NM_000135.4
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 16-89746833-TGAA-T is Pathogenic according to our data. Variant chr16-89746833-TGAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89746833-TGAA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.3403_3405del | p.Phe1135del | inframe_deletion | 34/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.3403_3405del | p.Phe1135del | inframe_deletion | 34/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.3403_3405del | p.Phe1135del | inframe_deletion | 34/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000212 AC: 3AN: 1413240Hom.: 0 AF XY: 0.00000286 AC XY: 2AN XY: 698630
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:2
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 03, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects FANCA function (PMID: 12444097). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 188384). This variant has been observed in individual(s) with clinical features of FANCA-related conditions (PMID: 10521298; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.3403_3405del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Phe1135del), but otherwise preserves the integrity of the reading frame. - |
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