rs11555217

Variant names:

• chr11-71441401-C-T
• rs11555217
• NM_001360.3:c.452G>A
• DHCR7 p.Trp151*

Your query was ambiguous. Multiple possible variants found:

• chr11-71441401-C-T
• chr11-71441401-C-A
• chr11-71441401-C-G

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_001360.3(DHCR7):​c.452G>A​(p.Trp151*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000711 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000373920: Functional studies demonstrated an absence of protein and no enzyme activity in HEK cells transfected with the variant (Witsch-Baumgartner et al. 2000)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00071 (0 hom.)
• Consequence: DHCR7 NM_001360.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40 O:2
• Conservation: PhyloP100: 6.89
• Publications: 61 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: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women's Health

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000373920: Functional studies demonstrated an absence of protein and no enzyme activity in HEK cells transfected with the variant (Witsch-Baumgartner et al. 2000).; SCV000329333: Studies of patient fibroblasts demonstrated that the transcript with this variant underwent nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease (Correa-Cerro et al., 2005b); PMID: 10995508, 25525159, 29300326, 27415407, 19390132, 22975760, 11175299, 16687448, 16678134, 15805162, 11078571, 27066502, 26685159, 9653161, 28166604, 29165578, 28250423, 15521979, 16497572, 20556518, 23293579, 10677299, 17965227, 29433144, 30609409, 31980526, 31589614
• PP5: Variant 11-71441401-C-T is Pathogenic according to our data. Variant chr11-71441401-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.452G>A	p.Trp151*	stop_gained	Exon 6 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.452G>A	p.Trp151*	stop_gained	Exon 6 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.488G>A	p.Trp163*	stop_gained	Exon 6 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.452G>A	p.Trp151*	stop_gained	Exon 6 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.452G>A	p.Trp151*	stop_gained	Exon 6 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.-134G>A		5_prime_UTR	Exon 5 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000769 AC: 192 AN: 249572 AF XY: 0.000814

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000894

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000714 AC: 1044 AN: 1461724 Hom.: 0 Cov.: 34 AF XY: 0.000780 AC XY: 567 AN XY: 727170

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000179 AC: 8 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000536 AC: 14 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000872 AC: 970 AN: 1111888

Other (OTH) AF: 0.000547 AC: 33 AN: 60384

GnomAD4 genome AF: 0.000677 AC: 103 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74350

African (AFR) AF: 0.000145 AC: 6 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68038

Other (OTH) AF: 0.000956 AC: 2 AN: 2092

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000627

EpiCase AF: 0.00202

EpiControl AF: 0.00107

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
28	-	-	Smith-Lemli-Opitz syndrome (30)
9	-	-	not provided (9)
1	-	-	DHCR7-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Small for gestational age;C1849185:Elevated circulating 7-dehydrocholesterol concentration;C2677180:Primary microcephaly;C4551570:2-3 toe syndactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		6.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs11555217;

hg19: chr11-71152447;