chr8-64596682-G-A

Variant names:

• chr8-64596682-G-A
• rs1394882103
• NM_004820.5:c.1481C>T

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.1481C>T​(p.Pro494Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P494Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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, 0.992

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.1481C>T	p.Pro494Leu	missense	Exon 6 of 6	NP_004811.1	O75881
	CYP7B1	NM_001324112.2		c.1234-6838C>T		intron	N/A	NP_001311041.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	ENST00000310193.4	TSL:1 MANE Select	c.1481C>T	p.Pro494Leu	missense	Exon 6 of 6	ENSP00000310721.3	O75881
	CYP7B1	ENST00000864436.1		c.1634C>T	p.Pro545Leu	missense	Exon 8 of 8	ENSP00000534495.1
	CYP7B1	ENST00000864435.1		c.1481C>T	p.Pro494Leu	missense	Exon 7 of 7	ENSP00000534494.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		10
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.86		Gain of MoRF binding (P = 0.1359)
MVP		0.95
MPC		0.45
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.89
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1394882103; hg19: chr8-65509239;