11-71435149-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001360.3(DHCR7):c.*226C>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 0.00805 in 691,308 control chromosomes in the GnomAD database, including 35 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 0.0065 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (31 hom.)
• Consequence: DHCR7 NM_001360.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0650

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003817439).
• BP6: Variant 11-71435149-G-A is Benign according to our data. Variant chr11-71435149-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 881160.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DHCR7	NM_001360.3	c.*226C>T		3_prime_UTR_variant	9/9	ENST00000355527.8
DHCR7	NM_001163817.2	c.*226C>T		3_prime_UTR_variant	9/9
DHCR7	XM_011544777.3	c.*417C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DHCR7	ENST00000355527.8	c.*226C>T		3_prime_UTR_variant	9/9	1	NM_001360.3	P1

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 997 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00843 AC: 1105 AN: 131060 Hom.: 7 AF XY: 0.00837 AC XY: 599 AN XY: 71554

Gnomad AFR exome AF: 0.00195

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00357

Gnomad FIN exome AF: 0.00314

Gnomad NFE exome AF: 0.0113

Gnomad OTH exome AF: 0.00893

GnomAD4 exome AF: 0.00848 AC: 4569 AN: 539020 Hom.: 31 Cov.: 4 AF XY: 0.00835 AC XY: 2439 AN XY: 291970

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.0368

Gnomad4 EAS exome AF: 0.0000321

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.00462

Gnomad4 NFE exome AF: 0.00976

Gnomad4 OTH exome AF: 0.00904

GnomAD4 genome AF: 0.00655 AC: 997 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00573 AC XY: 427 AN XY: 74464

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.0110 Hom.: 0

Bravo AF: 0.00658

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0132 AC: 51

ExAC AF: 0.00280 AC: 189

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Smith-Lemli-Opitz syndrome Uncertain:1

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. -

not provided Benign:1

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_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	3.0
Dann	Benign	0.43
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0038	T
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	N;N
PROVEAN	Benign	1.1	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
MVP		0.20
ClinPred		0.0050	T
GERP RS		-4.5
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: rs185557595; hg19: chr11-71146195;