rs776969626
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000135.4(FANCA):βc.4124_4125delβ(p.Thr1375SerfsTer49) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes π: 0.0000048 ( 0 hom. )
Consequence
FANCA
NM_000135.4 frameshift
NM_000135.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.494
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]
ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]
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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 16-89739174-CTG-C is Pathogenic according to our data. Variant chr16-89739174-CTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89739174-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.4124_4125del | p.Thr1375SerfsTer49 | frameshift_variant | 41/43 | ENST00000389301.8 | |
ZNF276 | NM_001113525.2 | c.*931_*932del | 3_prime_UTR_variant | 11/11 | ENST00000443381.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.4124_4125del | p.Thr1375SerfsTer49 | frameshift_variant | 41/43 | 1 | NM_000135.4 | P1 | |
ZNF276 | ENST00000443381.7 | c.*931_*932del | 3_prime_UTR_variant | 11/11 | 1 | NM_001113525.2 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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Cov.:
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250976Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135690
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461814Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727196
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 14, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 26, 2023 | - - |
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. - |
Fanconi anemia Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Feb 07, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Thr1375Serfs*49) in the FANCA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 81 amino acid(s) of the FANCA protein. This variant is present in population databases (rs776969626, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with Fanconi anemia (PMID: 21273304, 23934222, 27041517). ClinVar contains an entry for this variant (Variation ID: 552509). This variant disrupts the p.Arg1400 amino acid residue in FANCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15643609, 21273304, 24584348, 28102861, 28717661, 29098742). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2022 | Frameshift variant predicted to result in protein truncation, as the last 81 amino acids are replaced with 48 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 31589614, 24037726, 30792206, 28717661, 27041517, 21273304, 23934222, 26366677) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 19, 2018 | - - |
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