rs762402992
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_152419.3(HGSNAT):c.744-2A>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,607,888 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_152419.3 splice_acceptor, 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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HGSNAT | NM_152419.3 | c.744-2A>C | splice_acceptor_variant, intron_variant | ENST00000379644.9 | NP_689632.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HGSNAT | ENST00000379644.9 | c.744-2A>C | splice_acceptor_variant, intron_variant | 2 | NM_152419.3 | ENSP00000368965.4 | ||||
HGSNAT | ENST00000520704.1 | n.*193-2A>C | splice_acceptor_variant, intron_variant | 1 | ENSP00000429109.1 | |||||
HGSNAT | ENST00000522082.5 | c.-18A>C | upstream_gene_variant | 4 | ENSP00000430151.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455680Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 724608
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74358
ClinVar
Submissions by phenotype
Mucopolysaccharidosis, MPS-III-C;C4225287:Retinitis pigmentosa 73 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 04, 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1948100). Disruption of this splice site has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 19479962, 33879512). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 7 of the HGSNAT 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 HGSNAT are known to be pathogenic (PMID: 17033958, 19479962). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at