rs730882180
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_025074.7(FRAS1):c.7522+1G>T variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,046 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_025074.7 splice_donor
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FRAS1 | NM_025074.7 | c.7522+1G>T | splice_donor_variant | ENST00000512123.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FRAS1 | ENST00000512123.4 | c.7522+1G>T | splice_donor_variant | 5 | NM_025074.7 | P1 | |||
FRAS1 | ENST00000682513.1 | c.7522+1G>T | splice_donor_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240176Hom.: 0 AF XY: 0.00000768 AC XY: 1AN XY: 130278
GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1447046Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 717996
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Fraser syndrome 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 14, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 09, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 26, 2023 | 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. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (PMID: 17163535). ClinVar contains an entry for this variant (Variation ID: 2816). Disruption of this splice site has been observed in individual(s) with Fraser syndrome (PMID: 17163535). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 52 of the FRAS1 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 FRAS1 are known to be pathogenic (PMID: 12766769, 18671281). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at