chr6-35458438-C-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_021922.3(FANCE):c.1111C>T(p.Arg371Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,613,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. R371Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_021922.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCE | NM_021922.3 | c.1111C>T | p.Arg371Trp | missense_variant, splice_region_variant | 5/10 | ENST00000229769.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCE | ENST00000229769.3 | c.1111C>T | p.Arg371Trp | missense_variant, splice_region_variant | 5/10 | 1 | NM_021922.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152066Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000119 AC: 30AN: 251428Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135906
GnomAD4 exome AF: 0.0000643 AC: 94AN: 1461834Hom.: 0 Cov.: 32 AF XY: 0.0000729 AC XY: 53AN XY: 727232
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74274
ClinVar
Submissions by phenotype
Fanconi anemia complementation group E Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | May 26, 2023 | The FANCE c.1111C>T (p.Arg371Trp) missense variant has been reported in a homozygous state in at least four individuals with Fanconi anemia (PMIDs: 17924555; 36463940; 22778927). This variant is reported in the Genome Aggregation Database in nine alleles at a frequency of 0.000868 in the Ashkenazi Jewish population (version 2.1.1). Data from the FANCE crystal structure suggest p.Arg371Trp may destabilize ternary protein conformation and experiments using a yeast two hybrid system indicate the variant disrupts the interaction between FANCE and FANC2 within the FA complex (PMID: 17308347). Based on the available evidence, the c.1111C>T (p.Arg371Trp) variant is classified as likely pathogenic for Fanconi anemia. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 11, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 371 of the FANCE protein (p.Arg371Trp). This variant is present in population databases (rs775076977, gnomAD 0.08%). This missense change has been observed in individuals with Fanconi anemia (PMID: 17924555, 22778927; Invitae). ClinVar contains an entry for this variant (Variation ID: 566449). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FANCE function (PMID: 17308347). 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. - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Apr 08, 2012 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 26, 2021 | DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.1111C>T, in exon 5 that results in an amino acid change, p.Arg371Trp. This sequence change has been described in gnomAD with a frequency of 0.087% in the Ashkenazi Jewish sub-population (dbSNP rs775076977). The p.Arg371Trp change affects a moderately conserved amino acid residue located in a domain of the FANCE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg371Trp substitution. This sequence change has been reported in the homozygous state in several individuals with Fanconi anemia (PMID: 17924555, 22778927), as well as an individual affected with head and neck squamous cell carcinoma (PMID: 28678401). Functional studies have demonstrated that this missense change in disrupts FANCE–FANCD2 interaction in yeast (PMID: 17308347). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2023 | Reported in individuals with breast and/or ovarian cancer and an individual with head and neck squamous cell carcinoma (Maxwell et al., 2016; Chandrasekharappa et al., 2017; Jin et al., 2023); Published functional studies demonstrate a loss of interaction with FANCD2 in yeast (Nookala et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28678401, 33942288, 22778927, 19464302, 17924555, 17308347, 27153395, 36655350, 36845387, 32487094) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at