11-71437909-G-C

Variant names:

• chr11-71437909-G-C
• rs121909765
• NM_001360.3:c.866C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_001360.3(DHCR7):​c.866C>G​(p.Thr289Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T289I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.72
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001360.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71437909-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31940222).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.866C>G	p.Thr289Ser	missense_variant	Exon 8 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.866C>G	p.Thr289Ser	missense_variant	Exon 8 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.281C>G	p.Thr94Ser	missense_variant	Exon 7 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Uncertain	0.65	D;D;T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.68	.;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.34	N;N;.;.;.
PhyloP100		8.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.35	N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.69	T;T;T;T;T
Sift4G	Benign	0.74	T;T;T;T;.
Polyphen		0.0030	B;B;.;.;.
Vest4		0.31
MutPred		0.48		Loss of ubiquitination at K293 (P = 0.1388);Loss of ubiquitination at K293 (P = 0.1388);.;.;.;
MVP		0.95
MPC		0.11
ClinPred		0.61	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.50
Mutation Taster		=76/24	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: rs121909765; hg19: chr11-71148955;