16-90022730-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001481.3(GAS8):c.3+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,415,690 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )
Consequence
GAS8
NM_001481.3 splice_donor_region, intron
NM_001481.3 splice_donor_region, intron
Scores
1
1
Splicing: ADA: 0.00001141
2
Clinical Significance
Conservation
PhyloP100: -0.454
Genes affected
GAS8 (HGNC:4166): (growth arrest specific 8) This gene includes 11 exons spanning 25 kb and maps to a region of chromosome 16 that is sometimes deleted in breast and prostrate cancer. The second intron contains an apparently intronless gene, C16orf3, that is transcribed in the opposite orientation. This gene is a putative tumor suppressor gene. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000164 (25/152310) while in subpopulation AMR AF= 0.000588 (9/15306). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAS8 | NM_001481.3 | c.3+6C>T | splice_donor_region_variant, intron_variant | ENST00000268699.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAS8 | ENST00000268699.9 | c.3+6C>T | splice_donor_region_variant, intron_variant | 1 | NM_001481.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000138 AC: 9AN: 65314Hom.: 0 AF XY: 0.0000533 AC XY: 2AN XY: 37558
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GnomAD4 exome AF: 0.000109 AC: 138AN: 1263380Hom.: 1 Cov.: 31 AF XY: 0.000117 AC XY: 72AN XY: 616480
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GnomAD4 genome AF: 0.000164 AC: 25AN: 152310Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11AN XY: 74480
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 33 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 13, 2022 | This sequence change falls in intron 1 of the GAS8 gene. It does not directly change the encoded amino acid sequence of the GAS8 protein. It affects a nucleotide within the consensus splice site. 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 variant has not been reported in the literature in individuals affected with GAS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 542264). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at