12-57766073-C-T

Variant names:

• chr12-57766073-C-T
• rs28934604
• NM_000785.4:c.320G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000785.4(CYP27B1):​c.320G>A​(p.Arg107His) variant causes a missense change. The variant allele was found at a frequency of 0.00000428 in 1,402,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: CYP27B1 NM_000785.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.67
• Publications: 16 publications found

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]

CYP27B1 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 1A

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000785.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 12-57766073-C-T is Pathogenic according to our data. Variant chr12-57766073-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1658.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27B1	NM_000785.4	c.320G>A	p.Arg107His	missense_variant	Exon 2 of 9	ENST00000228606.9	NP_000776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9	c.320G>A	p.Arg107His	missense_variant	Exon 2 of 9	1	NM_000785.4	ENSP00000228606.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000428 AC: 6 AN: 1402074 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 693132

African (AFR) AF: 0.00 AC: 0 AN: 32442

American (AMR) AF: 0.00 AC: 0 AN: 37116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25240

East Asian (EAS) AF: 0.000135 AC: 5 AN: 37100

South Asian (SAS) AF: 0.00 AC: 0 AN: 80132

European-Finnish (FIN) AF: 0.0000248 AC: 1 AN: 40256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1085952

Other (OTH) AF: 0.00 AC: 0 AN: 58390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin D-dependent rickets, type 1A Pathogenic:1

Mar 05, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Vitamin D-dependent rickets, type 1 Pathogenic:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CYP27B1 c.320G>A (p.Arg107His) missense variant is reported in two studies in which it is found in three patients with vitamin D-dependent rickets, including in one patient who carried the variant in a homozygous state and in two brothers who were compound heterozygous for the p.Arg107His variant and a null variant (Kitanaka et al. 1998; Miyai et al. 2015). Control data are unavailable for this variant, which is not reported in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. The p.Arg107His variant was found to result in significantly reduced protein expression and no detectable protein activity as compared to wild type (Sawada et al. 1999; Sawada et al. 2001; Jacobs et al. 2013). Based on the evidence, the p.Arg107His variant is classified as likely pathogenic for vitamin D-dependent rickets. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.7
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.84		Gain of catalytic residue at C108 (P = 0.0055);
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		4.1
PromoterAI		0.042	Neutral
Varity_R		0.85
gMVP		0.70
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs28934604; hg19: chr12-58159856;