11-71434641-T-C

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.*734A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 164,736 control chromosomes in the GnomAD database, including 61,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.86 (56995 hom., cov: 29)
  • Exomes 𝑓: 0.83 (4551 hom.)
• Consequence: DHCR7 NM_001360.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.15

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=-0.93).
• BP6: Variant 11-71434641-T-C is Benign according to our data. Variant chr11-71434641-T-C is described in ClinVar as [Benign]. Clinvar id is 305936.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.*734A>G		3_prime_UTR_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.*734A>G		3_prime_UTR_variant	9/9
DHCR7	XM_011544777.3	c.*925A>G		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.*734A>G		3_prime_UTR_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130420 AN: 151712 Hom.: 57000 Cov.: 29

Gnomad AFR AF: 0.713

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.831

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.945

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.867

GnomAD4 exome AF: 0.828 AC: 10691 AN: 12906 Hom.: 4551 Cov.: 0 AF XY: 0.813 AC XY: 5704 AN XY: 7018

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.752

Gnomad4 ASJ exome AF: 0.787

Gnomad4 EAS exome AF: 0.799

Gnomad4 SAS exome AF: 0.592

Gnomad4 FIN exome AF: 0.911

Gnomad4 NFE exome AF: 0.930

Gnomad4 OTH exome AF: 0.855

GnomAD4 genome AF: 0.859 AC: 130438 AN: 151830 Hom.: 56995 Cov.: 29 AF XY: 0.856 AC XY: 63496 AN XY: 74192

Gnomad4 AFR AF: 0.711

Gnomad4 AMR AF: 0.830

Gnomad4 ASJ AF: 0.837

Gnomad4 EAS AF: 0.844

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.945

Gnomad4 NFE AF: 0.955

Gnomad4 OTH AF: 0.865

Alfa AF: 0.913 Hom.: 12984

Bravo AF: 0.845

Asia WGS AF: 0.695 AC: 2416 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 12, 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	-0.93
Cadd	Benign	0.60
Dann	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs7690; hg19: chr11-71145687;