NM_001360.3:c.1158T>C

Variant names:

• chr11-71435645-A-G
• rs760241
• NM_001360.3:c.1158T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001360.3(DHCR7):​c.1158T>C​(p.Asp386Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 1,612,582 control chromosomes in the GnomAD database, including 679,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (56400 hom., cov: 36)
  • Exomes 𝑓: 0.92 (623433 hom.)
• Consequence: DHCR7 NM_001360.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.535
• Publications: 32 publications found

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]

DHCR7 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.5435136E-7).
• BP6: Variant 11-71435645-A-G is Benign according to our data. Variant chr11-71435645-A-G is described in ClinVar as [Benign]. Clinvar id is 93707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.535 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1158T>C	p.Asp386Asp	synonymous_variant	Exon 9 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1158T>C	p.Asp386Asp	synonymous_variant	Exon 9 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.573T>C	p.Asp191Asp	synonymous_variant	Exon 8 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.853 AC: 129845 AN: 152178 Hom.: 56403 Cov.: 36

Gnomad AFR AF: 0.708

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.780

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.862

GnomAD2 exomes AF: 0.852 AC: 210542 AN: 247048 AF XY: 0.854

Gnomad AFR exome AF: 0.704

Gnomad AMR exome AF: 0.740

Gnomad ASJ exome AF: 0.844

Gnomad EAS exome AF: 0.786

Gnomad FIN exome AF: 0.946

Gnomad NFE exome AF: 0.949

Gnomad OTH exome AF: 0.879

GnomAD4 exome AF: 0.920 AC: 1342808 AN: 1460286 Hom.: 623433 Cov.: 85 AF XY: 0.914 AC XY: 663922 AN XY: 726546

African (AFR) AF: 0.696 AC: 23293 AN: 33476

American (AMR) AF: 0.748 AC: 33438 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.844 AC: 22048 AN: 26120

East Asian (EAS) AF: 0.798 AC: 31689 AN: 39686

South Asian (SAS) AF: 0.686 AC: 59186 AN: 86254

European-Finnish (FIN) AF: 0.945 AC: 49162 AN: 52008

Middle Eastern (MID) AF: 0.791 AC: 4560 AN: 5768

European-Non Finnish (NFE) AF: 0.959 AC: 1066034 AN: 1111914

Other (OTH) AF: 0.884 AC: 53398 AN: 60372

GnomAD4 genome AF: 0.853 AC: 129865 AN: 152296 Hom.: 56400 Cov.: 36 AF XY: 0.849 AC XY: 63218 AN XY: 74476

African (AFR) AF: 0.707 AC: 29378 AN: 41558

American (AMR) AF: 0.806 AC: 12338 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.833 AC: 2889 AN: 3468

East Asian (EAS) AF: 0.781 AC: 4039 AN: 5170

South Asian (SAS) AF: 0.675 AC: 3258 AN: 4826

European-Finnish (FIN) AF: 0.945 AC: 10051 AN: 10632

Middle Eastern (MID) AF: 0.823 AC: 242 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64938 AN: 68010

Other (OTH) AF: 0.860 AC: 1820 AN: 2116

Alfa AF: 0.905 Hom.: 57718

Bravo AF: 0.837

TwinsUK AF: 0.962 AC: 3568

ALSPAC AF: 0.959 AC: 3696

ESP6500AA AF: 0.725 AC: 3191

ESP6500EA AF: 0.946 AC: 8124

ExAC AF: 0.853 AC: 103424

Asia WGS AF: 0.650 AC: 2263 AN: 3478

EpiCase AF: 0.949

EpiControl AF: 0.948

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 06, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 25, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp386Asp in exon 9 of DHCR7: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 94.18% (61386/65178) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs760241). -

Smith-Lemli-Opitz syndrome Benign:5

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inborn genetic diseases Benign:1

Mar 11, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DHCR7-related disorder Benign:1

Apr 07, 2021

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	0.069
DANN	Benign	0.13
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	8.5e-7	T
MetaSVM	Benign	-0.88	T
PhyloP100		-0.54
PROVEAN	Benign	0.43	N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
ClinPred		0.022	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs760241; hg19: chr11-71146691; COSMIC: COSV62795292; COSMIC: COSV62795292;