rs72554620
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004820.5(CYP7B1):c.1162C>T(p.Arg388Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
CYP7B1
NM_004820.5 stop_gained
NM_004820.5 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.38
Genes affected
CYP7B1 (HGNC:2652): (cytochrome P450 family 7 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. This endoplasmic reticulum membrane protein catalyzes the first reaction in the cholesterol catabolic pathway of extrahepatic tissues, which converts cholesterol to bile acids. This enzyme likely plays a minor role in total bile acid synthesis, but may also be involved in the development of atherosclerosis, neurosteroid metabolism and sex hormone synthesis. Mutations in this gene have been associated with hereditary spastic paraplegia (SPG5 or HSP), an autosomal recessive disorder. [provided by RefSeq, Apr 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-64604753-G-A is Pathogenic according to our data. Variant chr8-64604753-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP7B1 | NM_004820.5 | c.1162C>T | p.Arg388Ter | stop_gained | 5/6 | ENST00000310193.4 | |
CYP7B1 | NM_001324112.2 | c.1162C>T | p.Arg388Ter | stop_gained | 5/7 | ||
CYP7B1 | XM_017014002.2 | c.1228C>T | p.Arg410Ter | stop_gained | 6/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP7B1 | ENST00000310193.4 | c.1162C>T | p.Arg388Ter | stop_gained | 5/6 | 1 | NM_004820.5 | P1 | |
CYP7B1 | ENST00000523954.1 | n.436C>T | non_coding_transcript_exon_variant | 3/5 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251456Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
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GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7AN XY: 727240
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 5A Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 27, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS4_MOD,PM2. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Paris Brain Institute, Inserm - ICM | - | - - |
Spastic paraplegia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 11, 2023 | This sequence change creates a premature translational stop signal (p.Arg388*) in the CYP7B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP7B1 are known to be pathogenic (PMID: 9802883, 19363635, 19439420, 21541746, 21567895, 28039895). This variant is present in population databases (rs72554620, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia and neonatal liver failure (PMID: 9802883, 18252231, 19812052). ClinVar contains an entry for this variant (Variation ID: 6100). For these reasons, this variant has been classified as Pathogenic. - |
Congenital bile acid synthesis defect 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2008 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at