rs139721775

Positions:

• chr11-71435462-G-A
• chr11-71435462-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001360.3(DHCR7):​c.1341C>T​(p.Asp447Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,612,632 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (19 hom.)
• Consequence: DHCR7 NM_001360.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.0200

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=-0.59).
• BP6: Variant 11-71435462-G-A is Benign according to our data. Variant chr11-71435462-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71435462-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00228 (3331/1460280) while in subpopulation MID AF= 0.0218 (126/5768). AF 95% confidence interval is 0.0187. There are 19 homozygotes in gnomad4_exome. There are 1740 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.1341C>T	p.Asp447Asp	synonymous_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.1341C>T	p.Asp447Asp	synonymous_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.*104C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.1341C>T	p.Asp447Asp	synonymous_variant	9/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.756C>T	p.Asp252Asp	synonymous_variant	8/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152234 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00549

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00393 AC: 978 AN: 248946 Hom.: 9 AF XY: 0.00376 AC XY: 508 AN XY: 135230

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.0360

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00320

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00672

GnomAD4 exome AF: 0.00228 AC: 3331 AN: 1460280 Hom.: 19 Cov.: 30 AF XY: 0.00239 AC XY: 1740 AN XY: 726518

Gnomad4 AFR exome AF: 0.00367

Gnomad4 AMR exome AF: 0.00555

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00342

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00537

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152352 Hom.: 4 Cov.: 33 AF XY: 0.00303 AC XY: 226 AN XY: 74492

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0351

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00458 Hom.: 2

Bravo AF: 0.00357

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00273

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	DHCR7: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2017	Variant summary: The DHCR7 c.1341C>T (p.Asp447Asp) variant involves the alteration of a non-conserved nucleotide causing a synonymous change and 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 399/117638 control chromosomes (6 homozygotes) at a frequency of 0.0033918, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301).Review publications, Jira_2003 and Wareham_2000, classify the variant as a "polymorphism," along with a publication indicating the variant to have been found in a cohort of SLOS patients and classified it as "polymorphism," as well as suggesting the variant may have co-occurred with a deleterious DHCR7 variant. In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Taken together, this variant is classified as "likely benign." -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28972118) -

Smith-Lemli-Opitz syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2019	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2016

This alteration is classified as likely 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

Nov 07, 2023

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	-0.59
CADD	Benign	6.5
DANN	Benign	0.77
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: rs139721775; hg19: chr11-71146508;