rs4646536

Variant names:

• chr12-57764205-A-G
• rs4646536
• NM_000785.4:c.1137-29T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000785.4(CYP27B1):​c.1137-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,594,334 control chromosomes in the GnomAD database, including 102,530 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8528 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94002 hom.)
• Consequence: CYP27B1 NM_000785.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 158 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27B1	NM_000785.4	c.1137-29T>C		intron_variant	Intron 6 of 8	ENST00000228606.9	NP_000776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1137-29T>C		intron_variant	Intron 6 of 8	1	NM_000785.4	ENSP00000228606.4

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49195 AN: 152066 Hom.: 8503 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.276

GnomAD2 exomes AF: 0.378 AC: 95027 AN: 251222 AF XY: 0.385

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.635

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.350 AC: 504508 AN: 1442148 Hom.: 94002 Cov.: 29 AF XY: 0.355 AC XY: 255381 AN XY: 718886

African (AFR) AF: 0.258 AC: 8545 AN: 33082

American (AMR) AF: 0.349 AC: 15602 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7500 AN: 26046

East Asian (EAS) AF: 0.701 AC: 27739 AN: 39598

South Asian (SAS) AF: 0.544 AC: 46746 AN: 85882

European-Finnish (FIN) AF: 0.358 AC: 19098 AN: 53408

Middle Eastern (MID) AF: 0.210 AC: 1200 AN: 5716

European-Non Finnish (NFE) AF: 0.327 AC: 357539 AN: 1093984

Other (OTH) AF: 0.344 AC: 20539 AN: 59750

GnomAD4 genome AF: 0.324 AC: 49269 AN: 152186 Hom.: 8528 Cov.: 33 AF XY: 0.331 AC XY: 24669 AN XY: 74420

African (AFR) AF: 0.270 AC: 11225 AN: 41528

American (AMR) AF: 0.278 AC: 4258 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 991 AN: 3466

East Asian (EAS) AF: 0.655 AC: 3390 AN: 5174

South Asian (SAS) AF: 0.558 AC: 2697 AN: 4832

European-Finnish (FIN) AF: 0.378 AC: 4002 AN: 10586

Middle Eastern (MID) AF: 0.161 AC: 47 AN: 292

European-Non Finnish (NFE) AF: 0.319 AC: 21714 AN: 67988

Other (OTH) AF: 0.282 AC: 596 AN: 2114

Alfa AF: 0.326 Hom.: 5082

Bravo AF: 0.311

Asia WGS AF: 0.599 AC: 2079 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.66
PhyloP100		0.18
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: rs4646536; hg19: chr12-58157988; COSMIC: COSV56985739; COSMIC: COSV56985739;