rs4646537

chr12-57763498-T-G

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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/exons	MANE	UniProt
CYP27B1	NM_000785.4	c.1413+113A>C		intron_variant		ENST00000228606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1413+113A>C		intron_variant		1	NM_000785.4	P1
CYP27B1	ENST00000713544.1	c.1494+113A>C		intron_variant
CYP27B1	ENST00000713545.1	c.*418+113A>C		intron_variant
CYP27B1	ENST00000547344.5	n.1552+113A>C		intron_variant, non_coding_transcript_variant		2

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

Gnomad4 AFR exome AF: 0.0916

Gnomad4 AMR exome AF: 0.0299

Gnomad4 ASJ exome AF: 0.0252

Gnomad4 EAS exome AF: 0.0291

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.0340

Gnomad4 NFE exome AF: 0.0354

Gnomad4 OTH exome AF: 0.0349

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

Gnomad4 AFR AF: 0.0846

Gnomad4 AMR AF: 0.0350

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.0300

Gnomad4 SAS AF: 0.0257

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0366

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.0410 Hom.: 83

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	13
Dann	Benign	0.50

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

LitVar

Other links and lift over

dbSNP: rs4646537; hg19: chr12-58157281;