rs8176345

Positions:

• chr12-57764775-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000785.4(CYP27B1):​c.942G>A​(p.Leu314=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,614,152 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 33)
  • Exomes 𝑓: 0.028 (671 hom.)
• Consequence: CYP27B1 NM_000785.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 12-57764775-C-T is Benign according to our data. Variant chr12-57764775-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 880899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3223/152272) while in subpopulation NFE AF= 0.0321 (2180/68000). AF 95% confidence interval is 0.0309. There are 49 homozygotes in gnomad4. There are 1465 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27B1	NM_000785.4	c.942G>A	p.Leu314=	synonymous_variant	5/9	ENST00000228606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27B1	ENST00000228606.9	c.942G>A	p.Leu314=	synonymous_variant	5/9	1	NM_000785.4	P1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3225 AN: 152154 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0210

Gnomad ASJ AF: 0.0749

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.00746

Gnomad FIN AF: 0.00725

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0321

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0231 AC: 5798 AN: 251472 Hom.: 98 AF XY: 0.0235 AC XY: 3197 AN XY: 135918

Gnomad AFR exome AF: 0.00548

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00738

Gnomad FIN exome AF: 0.00864

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0285 AC: 41606 AN: 1461880 Hom.: 671 Cov.: 33 AF XY: 0.0281 AC XY: 20463 AN XY: 727240

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0160

Gnomad4 ASJ exome AF: 0.0707

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00846

Gnomad4 FIN exome AF: 0.0102

Gnomad4 NFE exome AF: 0.0322

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0212 AC: 3223 AN: 152272 Hom.: 49 Cov.: 33 AF XY: 0.0197 AC XY: 1465 AN XY: 74438

Gnomad4 AFR AF: 0.00548

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0749

Gnomad4 EAS AF: 0.000966

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00725

Gnomad4 NFE AF: 0.0321

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0331 Hom.: 238

Bravo AF: 0.0225

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0378

EpiControl AF: 0.0388

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Vitamin D-dependent rickets, type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.44
CADD	Benign	9.7
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs8176345; hg19: chr12-58158558;