rs1365019056
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000135.4(FANCA):c.522+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000126 in 1,588,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000135.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCA | NM_000135.4 | c.522+1G>T | splice_donor_variant, intron_variant | Intron 5 of 42 | ENST00000389301.8 | NP_000126.2 | ||
FANCA | NM_001286167.3 | c.522+1G>T | splice_donor_variant, intron_variant | Intron 5 of 42 | NP_001273096.1 | |||
FANCA | NM_001018112.3 | c.522+1G>T | splice_donor_variant, intron_variant | Intron 5 of 10 | NP_001018122.1 | |||
FANCA | NM_001351830.2 | c.426+223G>T | intron_variant | Intron 4 of 9 | NP_001338759.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251450Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 6.96e-7 AC: 1AN: 1436688Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 716318
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152144Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
Fanconi anemia Pathogenic:1
This sequence change affects a donor splice site in intron 5 of the FANCA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FANCA are known to be pathogenic (PMID: 19367192). This variant is present in population databases (no rsID available, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Fanconi Anemia (PMID: 29098742). ClinVar contains an entry for this variant (Variation ID: 557826). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Fanconi anemia complementation group A Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at