rs1555146436

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001360.3(DHCR7):​c.536C>T​(p.Pro179Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DHCR7
NM_001360.3 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.72
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 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.536C>T p.Pro179Leu missense_variant 6/9 ENST00000355527.8 NP_001351.2 Q9UBM7A0A024R5F7
DHCR7NM_001163817.2 linkuse as main transcriptc.536C>T p.Pro179Leu missense_variant 6/9 NP_001157289.1 Q9UBM7A0A024R5F7
DHCR7XM_011544777.3 linkuse as main transcriptc.536C>T p.Pro179Leu missense_variant 6/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.536C>T p.Pro179Leu missense_variant 6/91 NM_001360.3 ENSP00000347717.4 Q9UBM7
DHCR7ENST00000685320.1 linkuse as main transcriptc.-50C>T 5_prime_UTR_variant 5/8 ENSP00000509319.1 B4E1K5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylFeb 05, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.53
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;.
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.89
D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.2
M;M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-2.9
D;D;D
REVEL
Pathogenic
0.86
Sift
Benign
0.059
T;T;D
Sift4G
Benign
0.073
T;T;.
Polyphen
0.97
D;D;.
Vest4
0.89
MutPred
0.65
Loss of helix (P = 0.3949);Loss of helix (P = 0.3949);.;
MVP
0.96
MPC
0.50
ClinPred
0.97
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.45
gMVP
0.98

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: rs1555146436; hg19: chr11-71152363; API