rs769547477
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_004629.2(FANCG):c.1077-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,652 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
Consequence
NM_004629.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCG | NM_004629.2 | c.1077-2A>G | splice_acceptor_variant | ENST00000378643.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCG | ENST00000378643.8 | c.1077-2A>G | splice_acceptor_variant | 1 | NM_004629.2 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250236Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135398
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461652Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727104
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Fanconi anemia complementation group G Pathogenic:6
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Avani P. Solanki, Daniela Pilonetto, Johan de Winter. - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Mar 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 27, 2021 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 moderate, PM2 moderate, PM3 moderate, PP1 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 21, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2022 | Published functional studies demonstrate a damaging effect (exon skipping or usage of a cryptic splice donor site leading to multiple aberrant transcripts) (Auerbach et al., 2003); This variant is associated with the following publications: (PMID: 25525159, 11438206, 33718801, 11093276, 12552564) - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 09, 2021 | PVS1, PS3, PM2 - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change affects an acceptor splice site in intron 8 of the FANCG gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs769547477, gnomAD 0.009%). Disruption of this splice site has been observed in individuals with Fanconi anaemia (PMID: 11093276, 12552564, 28717661). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 445394). Studies have shown that disruption of this splice site results in skipping of exon 9 and activation of a cryptic splice site and introduces a premature termination codon (PMID: 11093276). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at