chr22-36763918-C-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001177701.3(IFT27):c.352+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000586 in 1,604,688 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001177701.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251452Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135912
GnomAD4 exome AF: 0.0000620 AC: 90AN: 1452478Hom.: 0 Cov.: 29 AF XY: 0.0000608 AC XY: 44AN XY: 723356
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74376
ClinVar
Submissions by phenotype
IFT27-related disorder Pathogenic:1
The IFT27 c.349+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. On an alternate transcript (NM_001177701.2), this variant is referred to as c.352+1G>T. This variant was reported in the compound heterozygous state in two individuals with features consistent with Bardet-Biedl syndrome (Schaefer et al. 2019. PubMed ID: 30761183; Quélin et al. 2018. PubMed ID: 29704304). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-37159962-C-A). Variants that disrupt the consensus splice donor site in IFT27 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -
not provided Pathogenic:1
This sequence change affects a donor splice site in intron 5 of the IFT27 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs780659194, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with clinical features of IFT27-related conditions (PMID: 29704304, 30761183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.352+1G>T. ClinVar contains an entry for this variant (Variation ID: 585274). Studies have shown that disruption of this splice site results in skipping of exons 4-5 and 4-6, but is expected to preserve the integrity of the reading-frame (PMID: 30761183). For these reasons, this variant has been classified as Pathogenic. -
Bardet-Biedl syndrome 19 Pathogenic:1
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Bardet-Biedl syndrome Pathogenic:1
Mutation affecting splicing (functional study in submitter's publication) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at