11-71434732-G-A

Position:

• chr11-71434732-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001360.3(DHCR7):​c.*643C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.844 in 193,974 control chromosomes in the GnomAD database, including 70,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.84 (55089 hom., cov: 31)
  • Exomes 𝑓: 0.86 (15791 hom.)
• Consequence: DHCR7 NM_001360.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.49

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-71434732-G-A is Benign according to our data. Variant chr11-71434732-G-A is described in ClinVar as [Benign]. Clinvar id is 305940.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.*643C>T		3_prime_UTR_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.*643C>T		3_prime_UTR_variant	9/9
DHCR7	XM_011544777.3	c.*834C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.*643C>T		3_prime_UTR_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127870 AN: 151990 Hom.: 55091 Cov.: 31

Gnomad AFR AF: 0.666

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.803

Gnomad ASJ AF: 0.833

Gnomad EAS AF: 0.779

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.854

GnomAD4 exome AF: 0.857 AC: 35893 AN: 41866 Hom.: 15791 Cov.: 0 AF XY: 0.838 AC XY: 19063 AN XY: 22756

Gnomad4 AFR exome AF: 0.586

Gnomad4 AMR exome AF: 0.757

Gnomad4 ASJ exome AF: 0.807

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.649

Gnomad4 FIN exome AF: 0.935

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.884

GnomAD4 genome AF: 0.841 AC: 127892 AN: 152108 Hom.: 55089 Cov.: 31 AF XY: 0.838 AC XY: 62286 AN XY: 74342

Gnomad4 AFR AF: 0.665

Gnomad4 AMR AF: 0.803

Gnomad4 ASJ AF: 0.833

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.945

Gnomad4 NFE AF: 0.955

Gnomad4 OTH AF: 0.851

Alfa AF: 0.924 Hom.: 79002

Bravo AF: 0.824

Asia WGS AF: 0.650 AC: 2262 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Smith-Lemli-Opitz syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.61

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: rs1044535; hg19: chr11-71145778;