rs1223603615
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5
The NM_001360.3(DHCR7):c.532A>T(p.Ile178Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I178N) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
5
7
7
Clinical Significance
Conservation
PhyloP100: 5.30
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 transmembrane_region Helical (size 20) in uniprot entity DHCR7_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_001360.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-71441320-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.532A>T | p.Ile178Phe | missense_variant | 6/9 | ENST00000355527.8 | NP_001351.2 | |
DHCR7 | NM_001163817.2 | c.532A>T | p.Ile178Phe | missense_variant | 6/9 | NP_001157289.1 | ||
DHCR7 | XM_011544777.3 | c.532A>T | p.Ile178Phe | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.532A>T | p.Ile178Phe | missense_variant | 6/9 | 1 | NM_001360.3 | ENSP00000347717.4 | ||
DHCR7 | ENST00000685320.1 | c.-54A>T | 5_prime_UTR_variant | 5/8 | ENSP00000509319.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250988Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135724
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461886Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727244
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 20, 2024 | Variant summary: DHCR7 c.532A>T (p.Ile178Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250988 control chromosomes (gnomAD). c.532A>T has been reported in the literature in the compound heterozygous state in individuals affected with Smith-Lemli-Opitz Syndrome (e.g. Haas_2005, Witsch-Baumgartner_2005). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15776424, 16435228). ClinVar contains an entry for this variant (Variation ID: 558484). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Smith-Lemli-Opitz syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Pathogenic
Sift
Benign
T;T;T
Sift4G
Benign
T;T;.
Polyphen
P;P;.
Vest4
MutPred
Loss of stability (P = 0.2672);Loss of stability (P = 0.2672);.;
MVP
MPC
0.66
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
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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