rs10877012

Variant names:

• chr12-57768302-G-T
• rs10877012
• ENST00000546609.2:n.107+578C>A

Your query was ambiguous. Multiple possible variants found:

• chr12-57768302-G-T
• chr12-57768302-G-C

Variant summary

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

The ENST00000546609.2(CYP27B1):​n.107+578C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 151,968 control chromosomes in the GnomAD database, including 6,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: 𝑓 0.28 (6936 hom., cov: 32)
• Consequence: CYP27B1 ENST00000546609.2 intron
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: 0.153
• Publications: 213 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]

METTL1 (HGNC:7030): (methyltransferase 1, tRNA methylguanosine) This gene is similar in sequence to the S. cerevisiae YDL201w gene. The gene product contains a conserved S-adenosylmethionine-binding motif and is inactivated by phosphorylation. Alternative splice variants encoding different protein isoforms have been described for this gene. A pseudogene has been identified on chromosome X. [provided by RefSeq, Jul 2008]

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 = 0.632 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000546609.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	METTL1	NM_005371.6	MANE Select	c.*694C>A		downstream_gene	N/A	NP_005362.3	Q9UBP6-1
	METTL1	NM_023033.4		c.*872C>A		downstream_gene	N/A	NP_075422.3	Q9UBP6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27B1	ENST00000546609.2	TSL:5	n.107+578C>A		intron	N/A
	METTL1	ENST00000324871.12	TSL:1 MANE Select	c.*694C>A		downstream_gene	N/A	ENSP00000314441.7	Q9UBP6-1

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42276 AN: 151850 Hom.: 6932 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.253

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.278 AC: 42290 AN: 151968 Hom.: 6936 Cov.: 32 AF XY: 0.286 AC XY: 21262 AN XY: 74272

African (AFR) AF: 0.125 AC: 5185 AN: 41480

American (AMR) AF: 0.262 AC: 4003 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 988 AN: 3470

East Asian (EAS) AF: 0.650 AC: 3340 AN: 5138

South Asian (SAS) AF: 0.489 AC: 2357 AN: 4818

European-Finnish (FIN) AF: 0.378 AC: 3982 AN: 10548

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21512 AN: 67928

Other (OTH) AF: 0.251 AC: 529 AN: 2110

Alfa AF: 0.305 Hom.: 21345

Bravo AF: 0.262

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely risk allele

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Vitamin D-dependent rickets, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.60
PhyloP100		0.15

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10877012; hg19: chr12-58162085;