12-57763152-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000785.4(CYP27B1):c.1517T>G(p.Leu506Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP27B1 NM_000785.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27B1	NM_000785.4	c.1517T>G	p.Leu506Trp	missense_variant	9/9	ENST00000228606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1517T>G	p.Leu506Trp	missense_variant	9/9	1	NM_000785.4	P1
CYP27B1	ENST00000713544.1	c.1598T>G	p.Leu533Trp	missense_variant	9/9
CYP27B1	ENST00000713545.1	c.*522T>G		3_prime_UTR_variant	9/9
CYP27B1	ENST00000547344.5	n.1656T>G		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP27B1 protein function. This variant has not been reported in the literature in individuals affected with CYP27B1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 506 of the CYP27B1 protein (p.Leu506Trp). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	26
Dann	Benign	0.96
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.98	N
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.93	P
Vest4		0.22
MutPred		0.42		Gain of MoRF binding (P = 0.0049);
MVP		0.84
MPC		1.5
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.46
gMVP		0.86

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58156935;