rs372055524
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001360.3(DHCR7):c.1231G>A(p.Asp411Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000683 in 1,610,716 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 6.89
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 Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.932
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.1231G>A | p.Asp411Asn | missense_variant | 9/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.1231G>A | p.Asp411Asn | missense_variant | 9/9 | ||
DHCR7 | XM_011544777.3 | c.1365G>A | p.Ala455= | synonymous_variant | 9/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.1231G>A | p.Asp411Asn | missense_variant | 9/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 35
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GnomAD3 exomes AF: 0.0000122 AC: 3AN: 245912Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134000
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GnomAD4 exome AF: 0.00000549 AC: 8AN: 1458480Hom.: 0 Cov.: 85 AF XY: 0.00000413 AC XY: 3AN XY: 725704
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152236Hom.: 0 Cov.: 35 AF XY: 0.0000134 AC XY: 1AN XY: 74386
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Smith-Lemli-Opitz syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 27, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
T;T;T
Polyphen
D;D;.
Vest4
MVP
MPC
0.55
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