rs909217

Variant names:

• chr11-71435531-G-A
• rs909217
• NM_001360.3:c.1272C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-71435531-G-A
• chr11-71435531-G-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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.755
• Publications: 26 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 (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 VariationId is 93708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1272C>T	p.Gly424Gly	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.1272C>T	p.Gly424Gly	synonymous_variant	Exon 9 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.687C>T	p.Gly229Gly	synonymous_variant	Exon 8 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83967 AN: 152056 Hom.: 26078 Cov.: 35

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

GnomAD2 exomes AF: 0.560 AC: 137399 AN: 245264 AF XY: 0.554

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 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.: 83 AF XY: 0.673 AC XY: 488301 AN XY: 725648

African (AFR) AF: 0.293 AC: 9823 AN: 33474

American (AMR) AF: 0.528 AC: 23582 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 16355 AN: 26112

East Asian (EAS) AF: 0.349 AC: 13863 AN: 39682

South Asian (SAS) AF: 0.220 AC: 19012 AN: 86250

European-Finnish (FIN) AF: 0.589 AC: 29688 AN: 50374

Middle Eastern (MID) AF: 0.465 AC: 2680 AN: 5766

European-Non Finnish (NFE) AF: 0.763 AC: 848007 AN: 1111736

Other (OTH) AF: 0.630 AC: 37990 AN: 60310

GnomAD4 genome AF: 0.552 AC: 83991 AN: 152174 Hom.: 26082 Cov.: 35 AF XY: 0.537 AC XY: 39934 AN XY: 74408

African (AFR) AF: 0.313 AC: 13008 AN: 41512

American (AMR) AF: 0.518 AC: 7924 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2139 AN: 3470

East Asian (EAS) AF: 0.385 AC: 1988 AN: 5166

South Asian (SAS) AF: 0.210 AC: 1015 AN: 4828

European-Finnish (FIN) AF: 0.569 AC: 6038 AN: 10616

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50005 AN: 67974

Other (OTH) AF: 0.530 AC: 1121 AN: 2114

Alfa AF: 0.676 Hom.: 20060

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

Submissions by phenotype

Smith-Lemli-Opitz syndrome Benign:6

Oct 05, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Apr 11, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:4

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.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). -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

-

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

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_noAF	Benign	-0.54
CADD	Benign	0.59
DANN	Benign	0.74
PhyloP100		-0.76
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: rs909217; hg19: chr11-71146577; COSMIC: COSV62794705; COSMIC: COSV62794705;