rs121909767
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Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_001360.3(DHCR7):c.3G>A(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000013 in 1,613,968 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 start_lost
NM_001360.3 start_lost
Scores
8
4
3
Clinical Significance
Conservation
PhyloP100: 3.62
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_001360.3 (DHCR7) was described as [Likely_pathogenic] in ClinVar as 6794
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-71444950-C-T is Pathogenic according to our data. Variant chr11-71444950-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71444950-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.3G>A | p.Met1? | start_lost | 3/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.3G>A | p.Met1? | start_lost | 3/9 | ||
DHCR7 | XM_011544777.3 | c.3G>A | p.Met1? | start_lost | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.3G>A | p.Met1? | start_lost | 3/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251484Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135914
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727206
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152196Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74332
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 15, 2003 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 28, 2020 | Variant summary: DHCR7 c.3G>A (p.Met1?; p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. At-least one report describes evidence supporting alternative translation initiation from the downsteam Methionine codon 59 of the wild-type DHCR7 protein and that the first N-terminal 58 amino acids are not required for enzyme activity apriori (Wassif_1998). Another variant, c.1A>G (p.Met1?, reported as p.Met1Val) has also been reported in a patient with Smith-Lemli-Opitz Syndrome (Witsch-Baumgartner_2005). Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251484 control chromosomes. c.3G>A has been reported in the literature as a compound heterozygous genotype in at-least three individuals affected with milder clinical manifestations of Smith-Lemli-Opitz Syndrome (example, Waterham_2000, Langius_2003) and has been subsequently cited by others (example, Scalco_2005, Witsch-Baumgartner_2005, Correa-Cerro_2005, Jezela-Stanek_2008). These data indicate that the variant may be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One clinical diagnostic laboratory has submitted clinical significance assessment as likely pathogenic to ClinVar before 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6791). Disruption of the initiator codon has been observed in individual(s) with Smith–Lemli–Opitz syndrome (PMID: 12949967). This variant is present in population databases (rs121909767, gnomAD 0.0009%). This sequence change affects the initiator methionine of the DHCR7 mRNA. The next in-frame methionine is located at codon 59. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 07, 2014 | - - |
not provided Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2023 | As this variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12949967, 11111101, 23042628, 11767235, 11453964) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PROVEAN
Benign
N;N;N;N;N;N;N
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;.;.;D;.;D
Polyphen
P;P;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);Gain of catalytic residue at M1 (P = 0.0361);
MVP
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