rs35946774

Variant names:

• chr11-71435711-C-T
• rs35946774
• NM_001360.3:c.1092G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_001425112.1(DHCR7):​c.1226G>A​(p.Arg409Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,613,096 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 35)
  • Exomes 𝑓: 0.00055 (5 hom.)
• Consequence: DHCR7 NM_001425112.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.56
• Publications: 3 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 -11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 6 uncertain in NM_001425112.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0084937215).
• BP6: Variant 11-71435711-C-T is Benign according to our data. Variant chr11-71435711-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166985.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00563 (858/152354) while in subpopulation AFR AF = 0.0197 (818/41580). AF 95% confidence interval is 0.0186. There are 8 homozygotes in GnomAd4. There are 413 alleles in the male GnomAd4 subpopulation. Median coverage is 35. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001425112.1. 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.1092G>A	p.Thr364Thr	synonymous	Exon 9 of 9	NP_001351.2	A0A024R5F7
	DHCR7	NM_001425112.1		c.1226G>A	p.Arg409Gln	missense	Exon 9 of 9	NP_001412041.1
	DHCR7	NM_001425116.1		c.1130G>A	p.Arg377Gln	missense	Exon 9 of 9	NP_001412045.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHCR7	ENST00000355527.8	TSL:1 MANE Select	c.1092G>A	p.Thr364Thr	synonymous	Exon 9 of 9	ENSP00000347717.4	Q9UBM7
	DHCR7	ENST00000407721.6	TSL:1	c.1092G>A	p.Thr364Thr	synonymous	Exon 9 of 9	ENSP00000384739.2	Q9UBM7
	DHCR7	ENST00000685320.1		c.507G>A	p.Thr169Thr	synonymous	Exon 8 of 8	ENSP00000509319.1	B4E1K5

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 858 AN: 152236 Hom.: 8 Cov.: 35

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00150 AC: 374 AN: 248758 AF XY: 0.00114

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000724

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000549 AC: 802 AN: 1460742 Hom.: 5 Cov.: 37 AF XY: 0.000506 AC XY: 368 AN XY: 726680

African (AFR) AF: 0.0174 AC: 582 AN: 33476

American (AMR) AF: 0.000671 AC: 30 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000974 AC: 84 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52488

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1111844

Other (OTH) AF: 0.000961 AC: 58 AN: 60382

GnomAD4 genome AF: 0.00563 AC: 858 AN: 152354 Hom.: 8 Cov.: 35 AF XY: 0.00554 AC XY: 413 AN XY: 74514

African (AFR) AF: 0.0197 AC: 818 AN: 41580

American (AMR) AF: 0.00163 AC: 25 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00307 Hom.: 0

Bravo AF: 0.00635

ESP6500AA AF: 0.0209 AC: 92

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	2	Smith-Lemli-Opitz syndrome (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	8.2
DANN	Benign	0.81
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0085	T
MetaSVM	Uncertain	0.55	D
PhyloP100		-2.6
PROVEAN	Benign	0.26	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
MVP		0.42
ClinPred		0.016	T
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs35946774; hg19: chr11-71146757;