rs747851434
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000135.4(FANCA):c.3558_3559insG(p.Arg1187GlufsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,610,312 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1186R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000135.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.3558_3559insG | p.Arg1187GlufsTer28 | frameshift_variant | 36/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.3558_3559insG | p.Arg1187GlufsTer28 | frameshift_variant | 36/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.3558_3559insG | p.Arg1187GlufsTer28 | frameshift_variant | 36/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000122 AC: 3AN: 246388Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133792
GnomAD4 exome AF: 0.0000336 AC: 49AN: 1458212Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 725578
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74308
ClinVar
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 11, 2023 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1999 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Reported in ClinVar as pathogenic (ClinVar Variant ID# 3444; ClinVar); This variant is associated with the following publications: (PMID: 10431244, 17924555, 9399890, 31589614, 33718801, 24584348) - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This sequence change creates a premature translational stop signal (p.Arg1187Glufs*28) in the FANCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is present in population databases (rs747851434, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with Fanconi anemia (PMID: 9399890, 17924555, 24584348). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3444). For these reasons, this variant has been classified as Pathogenic. - |
FANCA-related condition Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 15, 2023 | The FANCA c.3558dupG variant is predicted to result in a frameshift and premature protein termination (p.Arg1187Glufs*28). In the literature this variant is also referred to as c.3559insG and c.3558_3559insG. This variant has been reported in the homozygous and presumed compound heterozygous states in individuals with Fanconi anemia (Savino et al. 1997. PubMed ID: 9399890; Ameziane et al. 2008. PubMed ID: 17924555). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-89811434-T-TC). Frameshift variants in FANCA are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at