11-71438991-T-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_001360.3(DHCR7):āc.719A>Gā(p.Asn240Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000247 in 1,614,108 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00018 ( 0 hom., cov: 34)
Exomes š: 0.00025 ( 0 hom. )
Consequence
DHCR7
NM_001360.3 missense
NM_001360.3 missense
Scores
7
9
2
Clinical Significance
Conservation
PhyloP100: 6.89
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 hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001360.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DHCR7 | NM_001360.3 | c.719A>G | p.Asn240Ser | missense_variant | 7/9 | ENST00000355527.8 | |
DHCR7 | NM_001163817.2 | c.719A>G | p.Asn240Ser | missense_variant | 7/9 | ||
DHCR7 | XM_011544777.3 | c.719A>G | p.Asn240Ser | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DHCR7 | ENST00000355527.8 | c.719A>G | p.Asn240Ser | missense_variant | 7/9 | 1 | NM_001360.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000184 AC: 28AN: 152232Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000159 AC: 40AN: 251374Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135908
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GnomAD4 exome AF: 0.000254 AC: 371AN: 1461758Hom.: 0 Cov.: 33 AF XY: 0.000260 AC XY: 189AN XY: 727166
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GnomAD4 genome AF: 0.000184 AC: 28AN: 152350Hom.: 0 Cov.: 34 AF XY: 0.000228 AC XY: 17AN XY: 74502
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 14, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 09, 2021 | PP3, PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2023 | DHCR7: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 23603282, 24813812) - |
Smith-Lemli-Opitz syndrome Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 03, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 240 of the DHCR7 protein (p.Asn240Ser). This variant is present in population databases (rs148609143, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DHCR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 445437). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 03, 2022 | Variant summary: DHCR7 c.719A>G (p.Asn240Ser) results in a 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 0.00016 in 251374 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DHCR7 causing Smith-Lemli-Opitz Syndrome (0.00016 vs 0.0043), allowing no conclusion about variant significance. c.719A>G has been reported in the literature in one individual affected with Cardiac defect (Hauser_2018). The report does not provide unequivocal conclusions about association of the variant with Smith-Lemli-Opitz Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2018 | The p.N240S variant (also known as c.719A>G), located in coding exon 5 of the DHCR7 gene, results from an A to G substitution at nucleotide position 719. The asparagine at codon 240 is replaced by serine, an amino acid with highly similar properties. In one study that aimed to determine the allele carrier frequency of Smith-Lemli-Opitz syndrome (SLOS), this variant was identified in the ESP population database cohort (Cross JL et al. Clin. Genet., 2015 Jun;87:570-5). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;T;D
Sift4G
Uncertain
D;D;D;.
Polyphen
D;D;.;.
Vest4
MVP
MPC
0.32
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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