rs786200926
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_001360.3(DHCR7):c.412+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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_001360.3 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.412+3A>T | splice_region_variant, intron_variant | Intron 5 of 8 | ENST00000355527.8 | NP_001351.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.412+3A>T | splice_region_variant, intron_variant | Intron 5 of 8 | 1 | NM_001360.3 | ENSP00000347717.4 | |||
DHCR7 | ENST00000685320.1 | c.-174+3A>T | splice_region_variant, intron_variant | Intron 4 of 7 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151946Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151946Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74218
ClinVar
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2010 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2021 | This variant has been observed in individual(s) with clinical features of Smith-Lemli-Opitz syndrome (PMID: 20635399). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 5 and introduces a premature termination codon (PMID: 20635399). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 30278). This variant is also known as IVS5+3A>T. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the DHCR7 gene. It does not directly change the encoded amino acid sequence of the DHCR7 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at