rs878854745

Positions:

• chr8-64624465-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004820.5(CYP7B1):​c.197C>G​(p.Pro66Arg) variant causes a missense change. 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 (★). Synonymous variant affecting the same amino acid position (i.e. P66P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP7B1	NM_004820.5	c.197C>G	p.Pro66Arg	missense_variant	2/6	ENST00000310193.4
CYP7B1	NM_001324112.2	c.197C>G	p.Pro66Arg	missense_variant	2/7
CYP7B1	XM_017014002.2	c.263C>G	p.Pro88Arg	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP7B1	ENST00000310193.4	c.197C>G	p.Pro66Arg	missense_variant	2/6	1	NM_004820.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 18, 2016

This variant is not present in population databases (ExAC no frequency). While it has not been reported in the literature, this variant has been observed to segregate with disease in an affected family tested at Invitae (Invitae database). In summary, this is a novel missense change with uncertain impact on protein function. Although this variant has been observed to segregate with disease in a family affected with HSP, the evidence is insufficient at this time to prove conclusively that it causes disease. For these reasons, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces proline with arginine at codon 66 of the CYP7B1 protein (p.Pro66Arg). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.64		Gain of MoRF binding (P = 0.0092);
MVP		0.87
MPC		0.45
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.75
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854745; hg19: chr8-65537022;