rs768520283
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000135.4(FANCA):āc.1899A>Cā(p.Glu633Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Consequence
NM_000135.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.1899A>C | p.Glu633Asp | missense_variant, splice_region_variant | 21/43 | ENST00000389301.8 | |
FANCA | NM_001286167.3 | c.1899A>C | p.Glu633Asp | missense_variant, splice_region_variant | 21/43 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FANCA | ENST00000389301.8 | c.1899A>C | p.Glu633Asp | missense_variant, splice_region_variant | 21/43 | 1 | NM_000135.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247448Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133714
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1458924Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725446
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74342
ClinVar
Submissions by phenotype
Fanconi anemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 633 of the FANCA protein (p.Glu633Asp). This variant is present in population databases (rs768520283, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FANCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 456089). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2023 | The c.1899A>C (p.E633D) alteration is located in exon 21 (coding exon 21) of the FANCA gene. This alteration results from a A to C substitution at nucleotide position 1899, causing the glutamic acid (E) at amino acid position 633 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Fanconi anemia complementation group A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at