rs547012639
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001360.3(DHCR7):c.1087C>T(p.Arg363Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,613,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000070 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
8
6
5
Clinical Significance
Conservation
PhyloP100: 4.54
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.816
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1087C>T | p.Arg363Cys | missense_variant | 9/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.1087C>T | p.Arg363Cys | missense_variant | 9/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.1221C>T | p.Ala407Ala | synonymous_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1087C>T | p.Arg363Cys | missense_variant | 9/9 | 1 | NM_001360.3 | ENSP00000347717.4 | ||
DHCR7 | ENST00000685320.1 | c.502C>T | p.Arg168Cys | missense_variant | 8/8 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152260Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.0000563 AC: 14AN: 248840Hom.: 0 AF XY: 0.0000592 AC XY: 8AN XY: 135164
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GnomAD4 exome AF: 0.0000698 AC: 102AN: 1460698Hom.: 0 Cov.: 37 AF XY: 0.0000729 AC XY: 53AN XY: 726660
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152378Hom.: 0 Cov.: 35 AF XY: 0.0000671 AC XY: 5AN XY: 74514
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 29, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 12270273) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 06, 2018 | - - |
Smith-Lemli-Opitz syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 10, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 02, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2023 | Variant summary: DHCR7 c.1087C>T (p.Arg363Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 248840 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (5.6e-05 vs 0.0043), allowing no conclusion about variant significance. c.1087C>T has been reported in the literature in at least one compound heterozygous individual affected with Smith-Lemli-Opitz Syndrome; the individual displayed a moderate phenotype and elevated 7DHC levels (Patrono_2002). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2019 | The p.R363C variant (also known as c.1087C>T), located in coding exon 7 of the DHCR7 gene, results from a C to T substitution at nucleotide position 1087. The arginine at codon 363 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in an individual suspicious for Smith-Lemli-Opitz syndrome who also carried the p.V330M variant; however, this individual did not have elevated levels of 7DHC and cholesterol levels were not measured (Patrono C et al. Mol. Cell. Probes, 2002 Aug;16:315-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MVP
MPC
0.32
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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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