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rs138659167

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_001360.3(DHCR7):c.964-1G>T variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0000444 in 1,599,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

DHCR7
NM_001360.3 splice_acceptor

Scores

4
2
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 6.89
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1
Splicing variant, LoF is a know mechanism of disease,
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-71435840-C-A is Pathogenic according to our data. Variant chr11-71435840-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 305956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435840-C-A is described in Lovd as [Likely_pathogenic]. Variant chr11-71435840-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DHCR7NM_001360.3 linkuse as main transcriptc.964-1G>T splice_acceptor_variant ENST00000355527.8
DHCR7NM_001163817.2 linkuse as main transcriptc.964-1G>T splice_acceptor_variant
DHCR7XM_011544777.3 linkuse as main transcriptc.1097G>T p.Arg366Met missense_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DHCR7ENST00000355527.8 linkuse as main transcriptc.964-1G>T splice_acceptor_variant 1 NM_001360.3 P1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152210
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000563
AC:
13
AN:
230702
Hom.:
0
AF XY:
0.0000627
AC XY:
8
AN XY:
127518
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:
0.000615
Gnomad NFE exome
AF:
0.0000290
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000435
AC:
63
AN:
1447660
Hom.:
0
Cov.:
36
AF XY:
0.0000417
AC XY:
30
AN XY:
718898
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:
0.000277
Gnomad4 NFE exome
AF:
0.0000434
Gnomad4 OTH exome
AF:
0.0000334
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152210
Hom.:
0
Cov.:
35
AF XY:
0.0000538
AC XY:
4
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000491
ExAC
AF:
0.0000498
AC:
6

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome Pathogenic:8
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.May 04, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017The DHCR7 c.964-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.964-1G>T variant, which is also described as IVS8-1G>T, has been reported in two studies in which it is identified in three patients with Smith-Lemli-Opitz syndrome (SLOS), including one homozygote and two compound heterozygotes (Jira et al. 2001; Weaver et al. 2008; Lanthaler et al. 2013). This variant was also found in a heterozygous state in the father of one patient, who had abnormally low cholesterol levels. Control data are unavailable for this variant, which is reported at a frequency of 0.00666 in the European (Finnish) population of the Exome Aggregation Consortium database. Jira et al. (2001) noted that the c.964-1G>T variant occurs at the same position as the known pathogenic c.964-1G>C splice acceptor variant, which accounts for over 28% of all disease-causing alleles in SLOS. The c.964-1G>C variant disrupts the splice acceptor site of intron eight, which leads to the insertion of 134 base pairs of intronic sequence into the DHCR7 mRNA causing a frameshift and premature truncation, ultimately resulting in a non-functional protein product. The c.964-1G>T variant is predicted to result in the same non-functional protein. Based on the evidence and due to the potential impact of splice acceptor variants, the c.964-1G>T variant is classified as likely pathogenic for Smith-Lemli-Opitz syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 29, 2018Variant summary: DHCR7 c.964-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6.6e-05 in 259000 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (6.6e-05 vs 0.0043), allowing no conclusion about variant significance. The variant, c.964-1G>T, has been reported in the literature in compound heterozygote and homozygote individuals affected with Smith-Lemli-Opitz Syndrome (Jira_2001, Weaver_2010, Lanthaler_2013). 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 11, 2023This sequence change affects an acceptor splice site in intron 8 of the DHCR7 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is present in population databases (rs138659167, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Smith–Lemli–Opitz Syndrome (PMID: 11427181, 20104611). ClinVar contains an entry for this variant (Variation ID: 305956). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.964-1G nucleotide in the DHCR7 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10814720, 10995508, 11427181, 23042628). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsDec 27, 2021- -
Pathogenic, no assertion criteria providedclinical testingCounsylAug 16, 2017- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaAug 19, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 22, 2022Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 20104611, 25525159, 28166604, 11427181, 22929031, 23042628) -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsNov 29, 2021The c.964-1G>T intronic alteration consists of a G to T substitution one nucleotide before coding exon 7 of the DHCR7 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). Based on data from gnomAD, the T allele has an overall frequency of 0.01% (17/262084) total alleles studied. The highest observed frequency was 0.05% (10/19724) of European (Finnish) alleles. This variant has been reported in the homozygous and compound heterozygous states in patients with Smith-Lemli-Opitz syndrome (SLOS) (Jira, 2001; Weaver, 2010; Lanthaler, 2013). In addition, another variant at this position (c.964-1G>C) is one of the most common DHCR7 mutations associated with SLOS (Witsch-Baumgartner, 2008). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. -
DHCR7-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 13, 2023The DHCR7 c.964-1G>T variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant was reported in an individual with Smith-Lemli-Opitz syndrome (described as IVS8-1G>T, Jira et al. 2001. PubMed ID: 11427181). This variant is reported in 0.051% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-71146886-C-A). Variants that disrupt the consensus splice acceptor site in DHCR7 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Uncertain
0.040
Cadd
Pathogenic
34
Dann
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
0.97
D
MutationTaster
Benign
1.0
D;D
ClinPred
0.46
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.56
Position offset: -31
DS_AL_spliceai
0.99
Position offset: -1

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: rs138659167; hg19: chr11-71146886; API