rs147424205

Variant names:

• chr11-71442276-G-A
• rs147424205
• ENST00000685320.1:c.-187C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000685320.1(DHCR7):​c.-187C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00304 in 1,613,048 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (17 hom.)
• Consequence: DHCR7 ENST00000685320.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: -0.739
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 11-71442276-G-A is Benign according to our data. Variant chr11-71442276-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197726.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000685320.1. 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.399C>T	p.Ala133Ala	synonymous	Exon 5 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.399C>T	p.Ala133Ala	synonymous	Exon 5 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.435C>T	p.Ala145Ala	synonymous	Exon 5 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000685320.1		c.-187C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 8	ENSP00000509319.1	B4E1K5
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.399C>T	p.Ala133Ala	synonymous	Exon 5 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.399C>T	p.Ala133Ala	synonymous	Exon 5 of 9	ENSP00000384739.2	Q9UBM7

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 371 AN: 152114 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00310 AC: 775 AN: 249860 AF XY: 0.00335

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00150

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00269

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00214

GnomAD4 exome AF: 0.00310 AC: 4526 AN: 1460816 Hom.: 17 Cov.: 31 AF XY: 0.00316 AC XY: 2298 AN XY: 726640

African (AFR) AF: 0.000568 AC: 19 AN: 33472

American (AMR) AF: 0.00112 AC: 50 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26074

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00346 AC: 298 AN: 86070

European-Finnish (FIN) AF: 0.00296 AC: 158 AN: 53350

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5756

European-Non Finnish (NFE) AF: 0.00335 AC: 3728 AN: 1111408

Other (OTH) AF: 0.00341 AC: 206 AN: 60338

GnomAD4 genome AF: 0.00244 AC: 371 AN: 152232 Hom.: 2 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74416

African (AFR) AF: 0.000578 AC: 24 AN: 41534

American (AMR) AF: 0.000785 AC: 12 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4826

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00401 AC: 273 AN: 67996

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00344 Hom.: 3

Bravo AF: 0.00215

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	4	Smith-Lemli-Opitz syndrome (5)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.8
DANN	Benign	0.57
PhyloP100		-0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs147424205; hg19: chr11-71153322; COSMIC: COSV100832223; COSMIC: COSV100832223;