11-71444036-G-C

Variant names:

• chr11-71444036-G-C
• NM_001360.3:c.278C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001360.3(DHCR7):​c.278C>G​(p.Thr93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T93M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DHCR7 NM_001360.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.93

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-71444036-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DHCR7	NM_001360.3	c.278C>G	p.Thr93Arg	missense_variant	Exon 4 of 9	ENST00000355527.8	NP_001351.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DHCR7	ENST00000355527.8	c.278C>G	p.Thr93Arg	missense_variant	Exon 4 of 9	1	NM_001360.3	ENSP00000347717.4
DHCR7	ENST00000685320.1	c.-308C>G		5_prime_UTR_variant	Exon 3 of 8			ENSP00000509319.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;D;.;T;T;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	.;T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.020	D;D;D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;.;.;D;.;.
Polyphen		0.99	D;D;.;.;.;.;.
Vest4		0.36
MutPred		0.53		Gain of MoRF binding (P = 0.0431);Gain of MoRF binding (P = 0.0431);.;Gain of MoRF binding (P = 0.0431);Gain of MoRF binding (P = 0.0431);Gain of MoRF binding (P = 0.0431);.;
MVP		0.94
MPC		0.52
ClinPred		0.93	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-71155082;