rs1223603615

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The ENST00000355527.8(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. I178M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DHCR7
ENST00000355527.8 missense

Scores

5
7
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.30
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000355527.8
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 ClinVar as [Likely_pathogenic]. Clinvar id is 2137194.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.532A>T p.Ile178Phe missense_variant 6/9 ENST00000355527.8 NP_001351.2
DHCR7NM_001163817.2 linkuse as main transcriptc.532A>T p.Ile178Phe missense_variant 6/9 NP_001157289.1
DHCR7XM_011544777.3 linkuse as main transcriptc.532A>T p.Ile178Phe missense_variant 6/9 XP_011543079.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.532A>T p.Ile178Phe missense_variant 6/91 NM_001360.3 ENSP00000347717 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
250988
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135724
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461886
Hom.:
0
Cov.:
34
AF XY:
0.00000275
AC XY:
2
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 20, 2024Variant 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 submitterclinical testingCounsylMay 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.30
BayesDel_addAF
Pathogenic
0.46
D
BayesDel_noAF
Pathogenic
0.42
CADD
Benign
22
DANN
Benign
0.80
DEOGEN2
Uncertain
0.69
D;D;.
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
.;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Uncertain
0.71
D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.6
M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.75
T
PROVEAN
Benign
-0.31
N;N;N
REVEL
Pathogenic
0.70
Sift
Benign
0.10
T;T;T
Sift4G
Benign
0.36
T;T;.
Polyphen
0.95
P;P;.
Vest4
0.96
MutPred
0.62
Loss of stability (P = 0.2672);Loss of stability (P = 0.2672);.;
MVP
0.96
MPC
0.66
ClinPred
0.53
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.10
gMVP
0.96

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1223603615; hg19: chr11-71152367; API