11-71443959-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001360.3(DHCR7):​c.321+34C>A variant causes a intron 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. 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_001360.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.74
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Smith-Lemli-Opitz syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.03).
• BP6: Variant 11-71443959-G-T is Benign according to our data. Variant chr11-71443959-G-T is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.321+34C>A		intron	N/A	NP_001351.2
	DHCR7	NM_001425108.1		c.355C>A	p.Gln119Lys	missense splice_region	Exon 4 of 9	NP_001412037.1
	DHCR7	NM_001425113.1		c.259C>A	p.Gln87Lys	missense splice_region	Exon 4 of 9	NP_001412042.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.321+34C>A		intron	N/A	ENSP00000347717.4
	DHCR7	ENST00000407721.6	TSL:1	c.321+34C>A		intron	N/A	ENSP00000384739.2
	DHCR7	ENST00000685320.1		c.-265+34C>A		intron	N/A	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

GnomAD2 exomes AF: 0.0108 AC: 2383 AN: 220338 AF XY: 0.00787

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 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

African (AFR) AF: 0.164 AC: 5372 AN: 32718

American (AMR) AF: 0.00766 AC: 318 AN: 41508

Ashkenazi Jewish (ASJ) AF: 0.0000402 AC: 1 AN: 24906

East Asian (EAS) AF: 0.000102 AC: 4 AN: 39098

South Asian (SAS) AF: 0.000350 AC: 29 AN: 82752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51060

Middle Eastern (MID) AF: 0.00899 AC: 51 AN: 5674

European-Non Finnish (NFE) AF: 0.000283 AC: 306 AN: 1080526

Other (OTH) AF: 0.0111 AC: 653 AN: 58770

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

African (AFR) AF: 0.169 AC: 7025 AN: 41536

American (AMR) AF: 0.0176 AC: 270 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 67996

Other (OTH) AF: 0.0341 AC: 72 AN: 2112

Alfa AF: 0.0306 Hom.: 72

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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 28, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.010
DANN	Benign	0.86
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs76865413; hg19: chr11-71155005;