rs76865413

Variant names:

• chr11-71443959-G-T
• rs76865413
• NM_001360.3:c.321+34C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001425108.1(DHCR7):​c.355C>A​(p.Gln119Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00901 in 1,569,252 control chromosomes in the GnomAD database, including 1,115 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (611 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (504 hom.)
• Consequence: DHCR7 NM_001425108.1 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.74

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 11-71443959-G-T is Benign according to our data. Variant chr11-71443959-G-T is described in ClinVar as [Benign]. Clinvar id is 257965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.321+34C>A		intron_variant	Intron 4 of 8	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.321+34C>A		intron_variant	Intron 4 of 8	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-265+34C>A		intron_variant	Intron 3 of 7			ENSP00000509319.1

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7347 AN: 152122 Hom.: 593 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0344

GnomAD3 exomes AF: 0.0108 AC: 2383 AN: 220338 Hom.: 153 AF XY: 0.00787 AC XY: 936 AN XY: 118930

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.00649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000237

Gnomad SAS exome AF: 0.000256

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000437

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00475 AC: 6734 AN: 1417012 Hom.: 504 Cov.: 26 AF XY: 0.00408 AC XY: 2870 AN XY: 703752

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.00766

Gnomad4 ASJ exome AF: 0.0000402

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000350

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0487 AC: 7410 AN: 152240 Hom.: 611 Cov.: 32 AF XY: 0.0473 AC XY: 3519 AN XY: 74450

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.0176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0259 Hom.: 61

Bravo AF: 0.0558

Asia WGS AF: 0.0130 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Smith-Lemli-Opitz syndrome Benign:2

Feb 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.010
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs76865413; hg19: chr11-71155005;