rs199506852

Variant names:

• chr11-71435422-G-A
• rs199506852
• NM_001360.3:c.1381C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_001360.3(DHCR7):​c.1381C>T​(p.Arg461Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000645 in 1,612,604 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (1 hom.)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 6.84
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_001360.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.07333329).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.1381C>T	p.Arg461Cys	missense	Exon 9 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.1432C>T	p.Arg478Cys	missense	Exon 10 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.1417C>T	p.Arg473Cys	missense	Exon 9 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1381C>T	p.Arg461Cys	missense	Exon 9 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.1381C>T	p.Arg461Cys	missense	Exon 9 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.796C>T	p.Arg266Cys	missense	Exon 8 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000162 AC: 40 AN: 247346 AF XY: 0.000134

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000603 AC: 88 AN: 1460278 Hom.: 1 Cov.: 30 AF XY: 0.0000564 AC XY: 41 AN XY: 726496

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000957 AC: 38 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111968

Other (OTH) AF: 0.000480 AC: 29 AN: 60378

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

African (AFR) AF: 0.0000240 AC: 1 AN: 41584

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Smith-Lemli-Opitz syndrome (5)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.073	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.77
Sift	Benign	0.072	T
Sift4G	Uncertain	0.034	D
Polyphen		0.99	D
Vest4		0.31
MVP		0.98
MPC		0.18
ClinPred		0.13	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.87
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs199506852; hg19: chr11-71146468;