rs4316537

Positions:

• chr11-71444083-G-A
• chr11-71444083-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001360.3(DHCR7):​c.231C>T​(p.Thr77Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0698 in 1,613,310 control chromosomes in the GnomAD database, including 4,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (649 hom., cov: 33)
  • Exomes 𝑓: 0.068 (4048 hom.)
• Consequence: DHCR7 NM_001360.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -3.98

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-71444083-G-A is Benign according to our data. Variant chr11-71444083-G-A is described in ClinVar as [Benign]. Clinvar id is 93716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.231C>T	p.Thr77Thr	synonymous_variant	4/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.231C>T	p.Thr77Thr	synonymous_variant	4/9		NP_001157289.1
DHCR7	XM_011544777.3	c.231C>T	p.Thr77Thr	synonymous_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.231C>T	p.Thr77Thr	synonymous_variant	4/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-333-22C>T		intron_variant				ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.0871 AC: 13258 AN: 152136 Hom.: 647 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0673

Gnomad ASJ AF: 0.0889

Gnomad EAS AF: 0.0971

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0859

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0615

Gnomad OTH AF: 0.0939

GnomAD3 exomes AF: 0.0780 AC: 19441 AN: 249200 Hom.: 881 AF XY: 0.0806 AC XY: 10854 AN XY: 134728

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.0875

Gnomad EAS exome AF: 0.0961

Gnomad SAS exome AF: 0.130

Gnomad FIN exome AF: 0.0794

Gnomad NFE exome AF: 0.0646

Gnomad OTH exome AF: 0.0754

GnomAD4 exome AF: 0.0680 AC: 99345 AN: 1461056 Hom.: 4048 Cov.: 30 AF XY: 0.0702 AC XY: 51043 AN XY: 726718

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0389

Gnomad4 ASJ exome AF: 0.0886

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.0750

Gnomad4 NFE exome AF: 0.0592

Gnomad4 OTH exome AF: 0.0737

GnomAD4 genome AF: 0.0871 AC: 13260 AN: 152254 Hom.: 649 Cov.: 33 AF XY: 0.0893 AC XY: 6649 AN XY: 74436

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.0671

Gnomad4 ASJ AF: 0.0889

Gnomad4 EAS AF: 0.0973

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.0859

Gnomad4 NFE AF: 0.0615

Gnomad4 OTH AF: 0.0929

Alfa AF: 0.0683 Hom.: 508

Bravo AF: 0.0842

Asia WGS AF: 0.0790 AC: 272 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 05, 2017	- -
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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2013	- -

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 23, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.56
DANN	Benign	0.83
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

Other links and lift over

dbSNP: rs4316537; hg19: chr11-71155129; COSMIC: COSV62795300; COSMIC: COSV62795300;