11-71435256-C-T

Position:

• chr11-71435256-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001360.3(DHCR7):​c.*119G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,085,190 control chromosomes in the GnomAD database, including 114 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 0.011 (17 hom., cov: 33)
  • Exomes 𝑓: 0.011 (97 hom.)
• Consequence: DHCR7 NM_001360.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.39

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 11-71435256-C-T is Benign according to our data. Variant chr11-71435256-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 305949.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0108 (1645/152318) while in subpopulation NFE AF= 0.0135 (915/68028). AF 95% confidence interval is 0.0127. There are 17 homozygotes in gnomad4. There are 839 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.*119G>A		3_prime_UTR_variant	9/9	ENST00000355527.8	NP_001351.2
DHCR7	NM_001163817.2	c.*119G>A		3_prime_UTR_variant	9/9		NP_001157289.1
DHCR7	XM_011544777.3	c.*310G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527	c.*119G>A		3_prime_UTR_variant	9/9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320	c.*119G>A		3_prime_UTR_variant	8/8			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152200 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0299

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.0109 AC: 10166 AN: 932872 Hom.: 97 Cov.: 13 AF XY: 0.0109 AC XY: 5304 AN XY: 485204

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.00283

Gnomad4 FIN exome AF: 0.0316

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0108 AC: 1645 AN: 152318 Hom.: 17 Cov.: 33 AF XY: 0.0113 AC XY: 839 AN XY: 74490

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.0121

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0299

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0165 Hom.: 6

Bravo AF: 0.00937

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	DHCR7: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.23
DANN	Benign	0.45

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: rs151230950; hg19: chr11-71146302;