rs4646537

Variant names:

• chr12-57763498-T-G
• rs4646537
• NM_000785.4:c.1413+113A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000785.4(CYP27B1):​c.1413+113A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,023,504 control chromosomes in the GnomAD database, including 844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.048 (231 hom., cov: 32)
  • Exomes 𝑓: 0.035 (613 hom.)
• Consequence: CYP27B1 NM_000785.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24
• Publications: 24 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-57763498-T-G is Benign according to our data. Variant chr12-57763498-T-G is described in ClinVar as Benign. ClinVar VariationId is 1266201.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27B1	NM_000785.4	c.1413+113A>C		intron_variant	Intron 8 of 8	ENST00000228606.9	NP_000776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1413+113A>C		intron_variant	Intron 8 of 8	1	NM_000785.4	ENSP00000228606.4

Frequencies

GnomAD3 genomes AF: 0.0483 AC: 7342 AN: 152128 Hom.: 231 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.0351

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0402

GnomAD4 exome AF: 0.0352 AC: 30704 AN: 871258 Hom.: 613 AF XY: 0.0345 AC XY: 15786 AN XY: 457874

African (AFR) AF: 0.0916 AC: 1992 AN: 21742

American (AMR) AF: 0.0299 AC: 1300 AN: 43512

Ashkenazi Jewish (ASJ) AF: 0.0252 AC: 564 AN: 22386

East Asian (EAS) AF: 0.0291 AC: 1079 AN: 37058

South Asian (SAS) AF: 0.0284 AC: 2094 AN: 73630

European-Finnish (FIN) AF: 0.0340 AC: 1798 AN: 52810

Middle Eastern (MID) AF: 0.0255 AC: 80 AN: 3134

European-Non Finnish (NFE) AF: 0.0354 AC: 20375 AN: 576286

Other (OTH) AF: 0.0349 AC: 1422 AN: 40700

GnomAD4 genome AF: 0.0482 AC: 7339 AN: 152246 Hom.: 231 Cov.: 32 AF XY: 0.0466 AC XY: 3470 AN XY: 74448

African (AFR) AF: 0.0846 AC: 3510 AN: 41504

American (AMR) AF: 0.0350 AC: 536 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.0300 AC: 156 AN: 5192

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4826

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10620

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0366 AC: 2486 AN: 68012

Other (OTH) AF: 0.0397 AC: 84 AN: 2114

Alfa AF: 0.0410 Hom.: 93

Bravo AF: 0.0507

Asia WGS AF: 0.0280 AC: 96 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.50
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs4646537; hg19: chr12-58157281;