chr8-64616016-C-G

Variant names:

• chr8-64616016-C-G
• rs794727501
• NM_004820.5:c.525G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004820.5(CYP7B1):​c.525G>C​(p.Trp175Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 151,990 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 Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.94
• Publications: 0 publications found

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]

CYP7B1 Gene-Disease associations (from GenCC):

• CYP7B1-related disorder of oxysterol accumulation

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• congenital bile acid synthesis defect 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary spastic paraplegia 5A

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004820.5. 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
	CYP7B1	NM_004820.5	MANE Select	c.525G>C	p.Trp175Cys	missense	Exon 3 of 6	NP_004811.1	O75881
	CYP7B1	NM_001324112.2		c.525G>C	p.Trp175Cys	missense	Exon 3 of 7	NP_001311041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	ENST00000310193.4	TSL:1 MANE Select	c.525G>C	p.Trp175Cys	missense	Exon 3 of 6	ENSP00000310721.3	O75881
	CYP7B1	ENST00000864436.1		c.678G>C	p.Trp226Cys	missense	Exon 5 of 8	ENSP00000534495.1
	CYP7B1	ENST00000864435.1		c.525G>C	p.Trp175Cys	missense	Exon 4 of 7	ENSP00000534494.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74228

African (AFR) AF: 0.0000242 AC: 1 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-12	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.83		Loss of ubiquitination at K171 (P = 0.0716)
MVP		0.89
MPC		0.55
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.90
Mutation Taster		=20/80	disease causing

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

Other links and lift over

dbSNP: rs794727501; hg19: chr8-65528573;