rs121917787
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001018115.3(FANCD2):c.904C>T(p.Arg302Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302P) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018115.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCD2 | NM_001018115.3 | c.904C>T | p.Arg302Trp | missense_variant | 12/44 | ENST00000675286.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCD2 | ENST00000675286.1 | c.904C>T | p.Arg302Trp | missense_variant | 12/44 | NM_001018115.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152112Hom.: 0 Cov.: 32 FAILED QC
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251276Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135820
GnomAD4 exome AF: 0.0000164 AC: 24AN: 1461772Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727196
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
ClinVar
Submissions by phenotype
Fanconi anemia complementation group D2 Pathogenic:5
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 02, 2019 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Nov 21, 2016 | - - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 302 of the FANCD2 protein (p.Arg302Trp). This variant is present in population databases (rs121917787, gnomAD 0.002%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 11239453, 22720145, 25703294; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12040). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCD2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects FANCD2 function (PMID: 11239453, 17308347, 22828868). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at