ENST00000546609.2:n.107+578C>A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_Strong

The ENST00000546609.2(CYP27B1):n.107+578C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: ENST00000546609.2 is not a MANE Select or MANE Plus Clinical transcript for CYP27B1; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.278 (AC=42,290) in the gnomAD database across 151,968 control chromosomes, including 6,936 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.632. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Uncertain Significance (no review 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: 26 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: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• vitamin D-dependent rickets, type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.632 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: ENST00000546609.2. You can select a different transcript below to see updated classification 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	Prot: NP_005362.3 UniProt:
	METTL1 NM_023033.4		c.*872C>A	downstream_gene	N/A	Prot: NP_075422.3 UniProt:

METTL1 NM_005371.6

MANE Select

HGVSc / HGVSpc.*694C>A

Exon rankN/A

downstream_gene

Prot: NP_005362.3UniProt: Q9UBP6-1

METTL1 NM_023033.4

HGVSc / HGVSpc.*872C>A

Exon rankN/A

downstream_gene

Prot: NP_075422.3UniProt: 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	Intron 1 of 3	Prot:
	METTL1 ENST00000324871.12	TSL:1MANE Select	c.*694C>A	downstream_gene	N/A	Prot: ENSP00000314441.7 UniProt:

CYP27B1 ENST00000546609.2

TSL:5

HGVSc / HGVSpn.107+578C>A

Exon rankIntron 1 of 3

intron

Prot:

METTL1 ENST00000324871.12

TSL:1MANE Select

HGVSc / HGVSpc.*694C>A

Exon rankN/A

downstream_gene

Prot: ENSP00000314441.7UniProt: Q9UBP6-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.278	AC:42276	Hom:6932	AN:151850	Cov:32
GnomAD4 genome	AF: 0.278	AC:42290	Hom:6936	AN:151968	Cov:32
TOPMed (Bravo)	AF: 0.262	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.303	AC:133988	Hom:21962	AN:442378	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.231	AC:542	Hom:74	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.629	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.403	AC:121	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.520	AC:1806	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.693	AC:5009	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.176	AC:31	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.771	AC:94584	Hom:36563	AN:122714	Cov:
Turkish Variome	AF: 0.286	AC:442	Hom:63	AN:1546	Cov:
UK10K	AF: 0.314	AC:2375	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.628	AC:5631	Hom:1750	AN:8960	Cov:

Showing 14 sources

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

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	4.3
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.60
GPN-Star LLR	N/A	-0.89
GPN-Star score	N/A	0.89
PhyloP100	Benign	0.15

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs10877012;

hg19: chr12-58162085;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar