rs567600444
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_001360.3(DHCR7):c.1091C>T(p.Thr364Met) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,613,132 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00016 ( 3 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
3
7
6
Clinical Significance
Conservation
PhyloP100: 4.62
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 Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.01763627).
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1091C>T | p.Thr364Met | missense_variant | 9/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.1091C>T | p.Thr364Met | missense_variant | 9/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.1225C>T | p.Arg409Trp | missense_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1091C>T | p.Thr364Met | missense_variant | 9/9 | 1 | NM_001360.3 | ENSP00000347717.4 | ||
DHCR7 | ENST00000685320.1 | c.506C>T | p.Thr169Met | missense_variant | 8/8 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 152250Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000346 AC: 86AN: 248776Hom.: 0 AF XY: 0.000489 AC XY: 66AN XY: 135102
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GnomAD4 exome AF: 0.000164 AC: 239AN: 1460764Hom.: 3 Cov.: 37 AF XY: 0.000256 AC XY: 186AN XY: 726702
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GnomAD4 genome AF: 0.000125 AC: 19AN: 152368Hom.: 0 Cov.: 34 AF XY: 0.000148 AC XY: 11AN XY: 74512
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Dec 26, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2022 | Has not been previously reported in peer-reviewed literature as pathogenic or benign to our knowledge. However, an abstract by Markholt et al. (2019) reported T364M in the homozygous state in a fetus with occipital encephalocele, although the variant was identified in the heterozygous state in a similarly affected related fetus and both fetuses also harbored a homozygous variant in the CSPP1 gene.; 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: 27535533, Markholt_2019_Abstract) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 14, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 23, 2016 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 25, 2016 | The p.T364M variant (also known as c.1091C>T), located in coding exon 7 of the DHCR7 gene, results from a C to T substitution at nucleotide position 1091. The threonine at codon 364 is replaced by methionine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6493 samples (12986 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
DHCR7-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 08, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Benign
T
MetaSVM
Pathogenic
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Pathogenic
D
MutPred
Loss of methylation at R198 (P = 0.02);
MVP
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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