rs759720450
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001360.3(DHCR7):c.1057del(p.Val353TrpfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 frameshift
NM_001360.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.525
Genes affected
DHCR7 (HGNC:2860): (7-dehydrocholesterol reductase) This gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. This gene is ubiquitously expressed and its transmembrane protein localizes to the endoplasmic reticulum membrane and nuclear outer membrane. Mutations in this gene cause Smith-Lemli-Opitz syndrome (SLOS); a syndrome that is metabolically characterized by reduced serum cholesterol levels and elevated serum 7-dehydrocholesterol levels and phenotypically characterized by cognitive disability, facial dysmorphism, syndactyly of second and third toes, and holoprosencephaly in severe cases to minimal physical abnormalities and near-normal intelligence in mild cases. Alternative splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, Aug 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 99 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-71435745-AC-A is Pathogenic according to our data. Variant chr11-71435745-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435745-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1057del | p.Val353TrpfsTer60 | frameshift_variant | 9/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.1057del | p.Val353TrpfsTer60 | frameshift_variant | 9/9 | ||
DHCR7 | XM_011544777.3 | c.1191del | p.Trp398GlyfsTer203 | frameshift_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1057del | p.Val353TrpfsTer60 | frameshift_variant | 9/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248962Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135256
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1459970Hom.: 0 Cov.: 37 AF XY: 0.0000110 AC XY: 8AN XY: 726144
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152242Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74380
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 12, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DHCR7 protein in which other variant(s) (p.Tyr382*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 551481). This premature translational stop signal has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 11111101). This variant is present in population databases (rs759720450, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Val353Trpfs*60) in the DHCR7 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 123 amino acid(s) of the DHCR7 protein. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at