chr11-71441283-G-A

Variant names:

• chr11-71441283-G-A
• rs74909468
• ENST00000685320.1:c.-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000685320.1(DHCR7):​c.-16C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,208 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (34 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (25 hom.)
• Consequence: DHCR7 ENST00000685320.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.57
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, ClinGen, Orphanet, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 11-71441283-G-A is Benign according to our data. Variant chr11-71441283-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 305957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1574/152324) while in subpopulation AFR AF = 0.0345 (1433/41560). AF 95% confidence interval is 0.033. There are 34 homozygotes in GnomAd4. There are 771 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000685320.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	NM_001360.3	MANE Select	c.570C>T	p.Ala190Ala	synonymous	Exon 6 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425107.1		c.570C>T	p.Ala190Ala	synonymous	Exon 6 of 10	NP_001412036.1	A0A804HI25
	DHCR7	NM_001425108.1		c.606C>T	p.Ala202Ala	synonymous	Exon 6 of 9	NP_001412037.1	A0A804HJQ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000685320.1		c.-16C>T		5_prime_UTR_premature_start_codon_gain	Exon 5 of 8	ENSP00000509319.1	B4E1K5
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.570C>T	p.Ala190Ala	synonymous	Exon 6 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.570C>T	p.Ala190Ala	synonymous	Exon 6 of 9	ENSP00000384739.2	Q9UBM7

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1539 AN: 152206 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00258 AC: 647 AN: 250524 AF XY: 0.00189

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000975

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00102 AC: 1489 AN: 1461884 Hom.: 25 Cov.: 34 AF XY: 0.000864 AC XY: 628 AN XY: 727242

African (AFR) AF: 0.0340 AC: 1138 AN: 33480

American (AMR) AF: 0.00268 AC: 120 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1112010

Other (OTH) AF: 0.00250 AC: 151 AN: 60394

GnomAD4 genome AF: 0.0103 AC: 1574 AN: 152324 Hom.: 34 Cov.: 33 AF XY: 0.0104 AC XY: 771 AN XY: 74486

African (AFR) AF: 0.0345 AC: 1433 AN: 41560

American (AMR) AF: 0.00758 AC: 116 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00640 Hom.: 9

Bravo AF: 0.0119

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Smith-Lemli-Opitz syndrome (4)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.27
DANN	Benign	0.72
PhyloP100		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs74909468; hg19: chr11-71152329;