rs1173704265
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000135.4(FANCA):āc.2534T>Cā(p.Leu845Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,494 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 (ā ā ). Synonymous variant affecting the same amino acid position (i.e. L845L) has been classified as Likely benign.
Frequency
Consequence
NM_000135.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.2534T>C | p.Leu845Pro | missense_variant | 27/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.2534T>C | p.Leu845Pro | missense_variant | 27/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.2534T>C | p.Leu845Pro | missense_variant | 27/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461222Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726974
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152272Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74396
ClinVar
Submissions by phenotype
Fanconi anemia complementation group A Pathogenic:3
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 08, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 08, 2024 | - - |
Fanconi anemia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 30, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FANCA function (PMID: 12444097). 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 FANCA protein function. ClinVar contains an entry for this variant (Variation ID: 556016). This missense change has been observed in individuals with Fanconi anemia (PMID: 12031647, 19367192, 22778927, 29098742). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 845 of the FANCA protein (p.Leu845Pro). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 21, 2017 | The c.2534T>C sequence change results in an amino acid change, p.Leu845Pro. This sequence change has not been observed in large population databases such as gnomAD. This pathogenic sequence change has previously been described in at least two patients with Fanconi anemia (Levran et al., 1997; Gille et al., 2012). The p.Leu845Pro change affects a moderately conserved amino acid residue located in a domain of the FANCA protein that is not known to be functional. Functional characterization of the p.Leu845Pro variant caused severe impairment of FANCA protein function, including abnormal cellular localization, weak phosphorylation and weak interaction with FANCC, FANCF and FANCD2 (Adachi et al., 2002). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at