rs72954276

chr11-71435791-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_001360.3(DHCR7):c.1012G>A(p.Val338Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000918 in 1,608,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00093 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -1.07

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01096943).
• BP6: Variant 11-71435791-C-T is Benign according to our data. Variant chr11-71435791-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93706.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.1012G>A	p.Val338Met	missense_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.1012G>A	p.Val338Met	missense_variant	9/9
DHCR7	XM_011544777.3	c.1146G>A	p.Pro382=	synonymous_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.1012G>A	p.Val338Met	missense_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152234 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000913 AC: 224 AN: 245410 Hom.: 1 AF XY: 0.000882 AC XY: 118 AN XY: 133858

Gnomad AFR exome AF: 0.000448

Gnomad AMR exome AF: 0.000785

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00314

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000954

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000933 AC: 1358 AN: 1455750 Hom.: 0 Cov.: 37 AF XY: 0.000937 AC XY: 678 AN XY: 723226

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00144

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000270

Gnomad4 NFE exome AF: 0.00106

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152352 Hom.: 0 Cov.: 35 AF XY: 0.000725 AC XY: 54 AN XY: 74504

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000956 Hom.: 2

Bravo AF: 0.000873

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000932 AC: 8

ExAC AF: 0.000825 AC: 100

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 31, 2018	This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2016	Variant summary: The DHCR7 c.1012G>A (p.Val338Met) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant. This variant was found in 99/113632 control chromosomes at a frequency of 0.0008712, which does not exceed the estimated maximal expected allele frequency of a pathogenic DHCR7 variant (0.0043301). In addition, one clinical diagnostic laboratory has classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 19, 2018

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2022

This variant is classified as likely 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
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	0.098
Dann	Benign	0.89
DEOGEN2	Uncertain	0.78	D;D;D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.069	N
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;N;N
REVEL	Benign	0.26
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.025	B;B;.
Vest4		0.066
MVP		0.68
MPC		0.15
ClinPred		0.0029	T
GERP RS		-7.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.025
gMVP		0.64

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: rs72954276; hg19: chr11-71146837;