12-57763065-C-T

Position:

• chr12-57763065-C-T

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.*77G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,017,624 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (189 hom.)
• Consequence: CYP27B1 NM_000785.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.273

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=-0.9).
• BP6: Variant 12-57763065-C-T is Benign according to our data. Variant chr12-57763065-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 884182.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27B1	NM_000785.4	c.*77G>A		3_prime_UTR_variant	9/9	ENST00000228606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27B1	ENST00000228606.9	c.*77G>A		3_prime_UTR_variant	9/9	1	NM_000785.4	P1
CYP27B1	ENST00000713544.1	c.*77G>A		3_prime_UTR_variant	9/9
CYP27B1	ENST00000713545.1	c.*609G>A		3_prime_UTR_variant	9/9
CYP27B1	ENST00000547344.5	n.1743G>A		non_coding_transcript_exon_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 504 AN: 152170 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0630

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00680 AC: 5882 AN: 865336 Hom.: 189 Cov.: 12 AF XY: 0.00903 AC XY: 4059 AN XY: 449264

Gnomad4 AFR exome AF: 0.000643

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.0000457

Gnomad4 EAS exome AF: 0.000431

Gnomad4 SAS exome AF: 0.0600

Gnomad4 FIN exome AF: 0.000502

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00603

GnomAD4 genome AF: 0.00331 AC: 504 AN: 152288 Hom.: 12 Cov.: 33 AF XY: 0.00412 AC XY: 307 AN XY: 74452

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0631

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00404 Hom.: 13

Bravo AF: 0.00179

Asia WGS AF: 0.0360 AC: 123 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin D-dependent rickets, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.56

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: rs8176350; hg19: chr12-58156848;