rs140748737

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001360.3(DHCR7):c.99-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0116 in 1,575,646 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0098 ( 11 hom., cov: 32)

Exomes 𝑓: 0.012 ( 130 hom. )

Consequence

DHCR7
NM_001360.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0005067

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -1.20

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00608477).

BP6

Variant 11-71444219-C-T is Benign according to our data. Variant chr11-71444219-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-71444219-C-T is described in Lovd as [Likely_pathogenic]. Variant chr11-71444219-C-T is described in Lovd as [Likely_benign]. Variant chr11-71444219-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00982 (1495/152270) while in subpopulation NFE AF= 0.016 (1085/68006). AF 95% confidence interval is 0.0152. There are 11 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DHCR7	NM_001360.3 linkuse as main transcript	c.99-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000355527.8
DHCR7	NM_001163817.2 linkuse as main transcript	c.99-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DHCR7	XM_011544777.3 linkuse as main transcript	c.99-4G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8 linkuse as main transcript	c.99-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001360.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00983

AC:

1495

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00386

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.00975

AC:

1824

AN:

187140

Hom.:

AF XY:

0.0102

AC XY:

1016

AN XY:

99682

show subpopulations

Gnomad AFR exome

AF:

0.00187

Gnomad AMR exome

AF:

0.00264

Gnomad ASJ exome

AF:

0.00446

Gnomad EAS exome

AF:

0.00150

Gnomad SAS exome

AF:

0.00550

Gnomad FIN exome

AF:

0.0160

Gnomad NFE exome

AF:

0.0153

Gnomad OTH exome

AF:

0.0118

GnomAD4 exome

AF:

0.0118

AC:

16736

AN:

1423376

Hom.:

130

Cov.:

AF XY:

0.0117

AC XY:

8224

AN XY:

704398

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.00404

Gnomad4 EAS exome

AF:

0.00936

Gnomad4 SAS exome

AF:

0.00545

Gnomad4 FIN exome

AF:

0.0182

Gnomad4 NFE exome

AF:

0.0129

Gnomad4 OTH exome

AF:

0.0115

GnomAD4 genome

AF:

0.00982

AC:

1495

AN:

152270

Hom.:

Cov.:

AF XY:

0.00939

AC XY:

699

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00250

Gnomad4 AMR

AF:

0.00398

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.0163

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.00997

Alfa

AF:

0.0120

Hom.:

Bravo

AF:

0.00824

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.00341

AC:

ESP6500EA

AF:

0.0139

AC:

119

ExAC

AF:

0.00924

AC:

1106

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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.99-4G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 628/37018 control chromosomes (8 homozygotes) at a frequency of 0.0169647, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301), suggesting this variant is likely a benign polymorphism. The variant of interest has been reported in affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DHCR7: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2018	This variant is associated with the following publications: (PMID: 25040602, 23042628) -

Smith-Lemli-Opitz syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jul 05, 2017	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 16, 2013	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 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_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

Cadd

Benign

1.2

Dann

Benign

0.80

Eigen

Benign

-0.075

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0061

MetaSVM

Uncertain

-0.19

MutationTaster

Benign

0.56

N;N

PROVEAN

Benign

-0.24

REVEL

Benign

0.18

Sift

Benign

0.13

MVP

0.84

ClinPred

0.0014

GERP RS

-4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00051

dbscSNV1_RF

Benign

0.010

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