12-57763698-T-TGGGTGGG
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000785.4(CYP27B1):c.1319_1325dupCCCACCC(p.Phe443ProfsTer24) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CYP27B1
NM_000785.4 frameshift
NM_000785.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.83
Publications
16 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 1AInheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- vitamin D-dependent rickets, type 1Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 12-57763698-T-TGGGTGGG is Pathogenic according to our data. Variant chr12-57763698-T-TGGGTGGG is described in ClinVar as Pathogenic. ClinVar VariationId is 279798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000785.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| CYP27B1 | NM_000785.4 | MANE Select | c.1319_1325dupCCCACCC | p.Phe443ProfsTer24 | frameshift | Exon 8 of 9 | NP_000776.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CYP27B1 | ENST00000228606.9 | TSL:1 MANE Select | c.1319_1325dupCCCACCC | p.Phe443ProfsTer24 | frameshift | Exon 8 of 9 | ENSP00000228606.4 | ||
| CYP27B1 | ENST00000713544.1 | c.1400_1406dupCCCACCC | p.Phe470ProfsTer24 | frameshift | Exon 8 of 9 | ENSP00000518840.1 | |||
| CYP27B1 | ENST00000713545.1 | c.*324_*330dupCCCACCC | 3_prime_UTR | Exon 8 of 9 | ENSP00000518841.1 |
Frequencies
GnomAD3 genomes 0.000174 AC: 26AN: 149740Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
26
AN:
149740
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
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Gnomad ASJ
AF:
Gnomad EAS
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Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
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Gnomad NFE
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Gnomad OTH
AF:
GnomAD2 exomes AF: 0.000223 AC: 56AN: 251182 AF XY: 0.000162 show subpopulations
GnomAD2 exomes
AF:
AC:
56
AN:
251182
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
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Gnomad ASJ exome
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Gnomad EAS exome
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Gnomad FIN exome
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Gnomad NFE exome
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Gnomad OTH exome
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000213 AC: 298AN: 1400382Hom.: 0 Cov.: 38 AF XY: 0.000190 AC XY: 133AN XY: 699120 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
298
AN:
1400382
Hom.:
Cov.:
38
AF XY:
AC XY:
133
AN XY:
699120
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
6
AN:
32300
American (AMR)
AF:
AC:
18
AN:
44498
Ashkenazi Jewish (ASJ)
AF:
AC:
1
AN:
25576
East Asian (EAS)
AF:
AC:
8
AN:
38926
South Asian (SAS)
AF:
AC:
16
AN:
85038
European-Finnish (FIN)
AF:
AC:
1
AN:
52162
Middle Eastern (MID)
AF:
AC:
0
AN:
5628
European-Non Finnish (NFE)
AF:
AC:
235
AN:
1058246
Other (OTH)
AF:
AC:
13
AN:
58008
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.363
Heterozygous variant carriers
0
14
27
41
54
68
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
20
40
60
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100
<30
30-35
35-40
40-45
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Age
GnomAD4 genome 0.000174 AC: 26AN: 149854Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 8AN XY: 73186 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
26
AN:
149854
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
73186
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
2
AN:
40826
American (AMR)
AF:
AC:
3
AN:
15102
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3458
East Asian (EAS)
AF:
AC:
5
AN:
5016
South Asian (SAS)
AF:
AC:
2
AN:
4660
European-Finnish (FIN)
AF:
AC:
0
AN:
10296
Middle Eastern (MID)
AF:
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
AC:
13
AN:
67228
Other (OTH)
AF:
AC:
1
AN:
2074
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000240896), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.360
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Genome Het
Variant carriers
0
2
4
6
8
10
<30
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35-40
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60-65
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>80
Age
Alfa
AF:
Hom.:
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
10
-
-
Vitamin D-dependent rickets, type 1A (10)
4
-
-
not provided (4)
1
-
-
CYP27B1-related disorder (1)
1
-
-
Inborn genetic diseases (1)
1
-
-
Vitamin D-dependent rickets, type 1 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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