rs201466849

chr11-71442275-C-Achr11-71442275-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001360.3(DHCR7):c.400G>T(p.Val134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,612,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V134M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.0930

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043869883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.400G>T	p.Val134Leu	missense_variant	5/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.400G>T	p.Val134Leu	missense_variant	5/9
DHCR7	XM_011544777.3	c.400G>T	p.Val134Leu	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.400G>T	p.Val134Leu	missense_variant	5/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.000362 AC: 55 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.0000721 AC: 18 AN: 249662 Hom.: 0 AF XY: 0.0000519 AC XY: 7 AN XY: 134900

Gnomad AFR exome AF: 0.000810

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000288 AC: 42 AN: 1460628 Hom.: 0 Cov.: 31 AF XY: 0.0000317 AC XY: 23 AN XY: 726554

Gnomad4 AFR exome AF: 0.000926

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74388

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.0000448 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:3 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 04, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 25, 2022	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2022	Reported in an individual with SLOS in published literature; however, it is not known if this patient harbored a second variant in DHCR7 (Waterham et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23891399, 24813812, 23042628, 29300326) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2018	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2018

The p.V134L variant (also known as c.400G>T), located in coding exon 3 of the DHCR7 gene, results from a G to T substitution at nucleotide position 400. The valine at codon 134 is replaced by leucine, an amino acid with highly similar properties. This alteration was identified and considered causative in one study; however, no information regarding patient phenotype or second allele genotype was provided (Waterham HR et al. Am J Med Genet C Semin Med Genet, 2012 Nov;160C:263-84; Cross JL et al. Clin. Genet., 2015 Jun;87:570-5). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	6.3
Dann	Benign	0.94
DEOGEN2	Uncertain	0.65	D;D;.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.37	N
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.30	N;N;N;N
REVEL	Uncertain	0.64
Sift	Benign	0.38	T;T;T;T
Sift4G	Benign	0.87	T;T;.;.
Polyphen		0.38	B;B;.;.
Vest4		0.69
MutPred		0.35		Loss of disorder (P = 0.3108);Loss of disorder (P = 0.3108);.;Loss of disorder (P = 0.3108);
MVP		0.82
MPC		0.13
ClinPred		0.0033	T
GERP RS		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201466849; hg19: chr11-71153321;