rs909217

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001360.3(DHCR7):c.1272C>T(p.Gly424Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 1,610,536 control chromosomes in the GnomAD database, including 390,252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 26082 hom., cov: 35)

Exomes 𝑓: 0.69 ( 364170 hom. )

Consequence

DHCR7
NM_001360.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.755

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]

DHCR7 links:

DHCR7 (HGNC:):

DHCR7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 11-71435531-G-A is Benign according to our data. Variant chr11-71435531-G-A is described in ClinVar as [Benign]. Clinvar id is 93708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435531-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.755 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3 linkuse as main transcript	c.1272C>T	p.Gly424Gly	synonymous_variant	9/9	ENST00000355527.8	NP_001351.2	Q9UBM7A0A024R5F7
DHCR7	NM_001163817.2 linkuse as main transcript	c.1272C>T	p.Gly424Gly	synonymous_variant	9/9		NP_001157289.1	Q9UBM7A0A024R5F7
DHCR7	XM_011544777.3 linkuse as main transcript	c.*35C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.1272C>T	p.Gly424Gly	synonymous_variant	9/9	1	NM_001360.3	ENSP00000347717.4		Q9UBM7
DHCR7	ENST00000685320.1 linkuse as main transcript	c.687C>T	p.Gly229Gly	synonymous_variant	8/8			ENSP00000509319.1		B4E1K5

Frequencies

GnomAD3 genomes

AF:

0.552

AC:

83967

AN:

152056

Hom.:

26078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.673

Gnomad AMR

AF:

0.518

Gnomad ASJ

AF:

0.616

Gnomad EAS

AF:

0.384

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.736

Gnomad OTH

AF:

0.536

GnomAD3 exomes

AF:

0.560

AC:

137399

AN:

245264

Hom.:

42783

AF XY:

0.554

AC XY:

74165

AN XY:

133758

show subpopulations

Gnomad AFR exome

AF:

0.308

Gnomad AMR exome

AF:

0.529

Gnomad ASJ exome

AF:

0.624

Gnomad EAS exome

AF:

0.390

Gnomad SAS exome

AF:

0.214

Gnomad FIN exome

AF:

0.587

Gnomad NFE exome

AF:

0.715

Gnomad OTH exome

AF:

0.602

GnomAD4 exome

AF:

0.686

AC:

1001000

AN:

1458362

Hom.:

364170

Cov.:

AF XY:

0.673

AC XY:

488301

AN XY:

725648

show subpopulations

Gnomad4 AFR exome

AF:

0.293

Gnomad4 AMR exome

AF:

0.528

Gnomad4 ASJ exome

AF:

0.626

Gnomad4 EAS exome

AF:

0.349

Gnomad4 SAS exome

AF:

0.220

Gnomad4 FIN exome

AF:

0.589

Gnomad4 NFE exome

AF:

0.763

Gnomad4 OTH exome

AF:

0.630

GnomAD4 genome

AF:

0.552

AC:

83991

AN:

152174

Hom.:

26082

Cov.:

AF XY:

0.537

AC XY:

39934

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.313

Gnomad4 AMR

AF:

0.518

Gnomad4 ASJ

AF:

0.616

Gnomad4 EAS

AF:

0.385

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.569

Gnomad4 NFE

AF:

0.736

Gnomad4 OTH

AF:

0.530

Alfa

AF:

0.686

Hom.:

17792

Bravo

AF:

0.547

Asia WGS

AF:

0.277

AC:

967

AN:

3478

EpiCase

AF:

0.740

EpiControl

AF:

0.737

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Smith-Lemli-Opitz syndrome

Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 05, 2021	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly424Gly 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 69.38% (44295/63848) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs909217). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 06, 2018	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2021

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_noAF

Benign

-0.54

CADD

Benign

0.59

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over