rs1555146021

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000355527.8(DHCR7):ā€‹c.808A>Gā€‹(p.Met270Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,552 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 (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

DHCR7
ENST00000355527.8 missense

Scores

7
11
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U:1

Conservation

PhyloP100: 6.97
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 Pathogenic. Variant got 14 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000355527.8
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.842
PP5
Variant 11-71438902-T-C is Pathogenic according to our data. Variant chr11-71438902-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71438902-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.808A>G p.Met270Val missense_variant 7/9 ENST00000355527.8 NP_001351.2
DHCR7NM_001163817.2 linkuse as main transcriptc.808A>G p.Met270Val missense_variant 7/9 NP_001157289.1
DHCR7XM_011544777.3 linkuse as main transcriptc.808A>G p.Met270Val missense_variant 7/9 XP_011543079.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.808A>G p.Met270Val missense_variant 7/91 NM_001360.3 ENSP00000347717 P1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461552
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 12, 2023For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DHCR7 protein function. ClinVar contains an entry for this variant (Variation ID: 556307). This missense change has been observed in individual(s) with Smith-Lemli-Opitz syndrome (PMID: 18249054). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 270 of the DHCR7 protein (p.Met270Val). -
Uncertain significance, flagged submissionclinical testingCounsylJan 24, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 03, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.44
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.98
D;D;D;D;.
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.93
.;D;D;D;D
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Uncertain
2.7
M;M;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-2.5
D;D;D;N;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.013
D;D;D;D;D
Sift4G
Uncertain
0.014
D;D;D;D;.
Polyphen
0.96
D;D;.;.;.
Vest4
0.92
MutPred
0.59
Loss of catalytic residue at V266 (P = 0.0487);Loss of catalytic residue at V266 (P = 0.0487);.;.;.;
MVP
0.94
MPC
0.21
ClinPred
0.93
D
GERP RS
4.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.68
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1555146021; hg19: chr11-71149948; API