8-64604753-G-C

Variant names:

• chr8-64604753-G-C
• rs72554620
• NM_004820.5:c.1162C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_004820.5(CYP7B1):​c.1162C>G​(p.Arg388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R388Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYP7B1 NM_004820.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.38
• 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):

• congenital bile acid synthesis defect 3

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

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

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, 0.933
• PP5: Variant 8-64604753-G-C is Pathogenic according to our data. Variant chr8-64604753-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2428781.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	NM_004820.5	MANE Select	c.1162C>G	p.Arg388Gly	missense	Exon 5 of 6	NP_004811.1
	CYP7B1	NM_001324112.2		c.1162C>G	p.Arg388Gly	missense	Exon 5 of 7	NP_001311041.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7B1	ENST00000310193.4	TSL:1 MANE Select	c.1162C>G	p.Arg388Gly	missense	Exon 5 of 6	ENSP00000310721.3
	CYP7B1	ENST00000523954.1	TSL:3	n.436C>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 5A Pathogenic:1

Feb 06, 2023

Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CYP7B1 gene has been associated with autosomal recessive spastic paraplegia 5A (OMIM#270800) and autosomal recessive congenital bile acid synthesis defect (OMIM#613812). The latter has been reported in rare cases where the majority of mutations are nonsense or frameshift in nature (PMID: 35580280). The c.1162C>G variant is detected in a presumed homozygous state in a HSP patient presenting with toe walking, LL pyrimidal weakness and spasticity with brisk reflexes, clonus. It is novel, not reported in population database (gnomAD) and has not been associated with HSP previously. The missense substitution predicts an amino acid change from arginine to glycine in position 388 in the CYP7B1 protein, p.(Arg388Gly). Another missense change (p.Arg388Gln) at the same protein location has been reported in a compound heterozygous state in a patient affected with HSP. Their diagnosis was supported by the typical increase of plasma oxysterols caused by pathogenic variants in CYP7B1 (PMID: 29228183). This variation is located in the cytochrome P450 E-class group IV domain and substitutes a highly conserved amino acid. The mutant residue is predicted to affect the formation of hydrogen bonds and salt bridges with several amino acids made by the wild-type residue. Glycine is very flexible and can disturb the required rigidity of the protein at this position. In silico analysis by REVEL predicts the effect of the variant as uncertain (REVEL:0.653), while MetaRNN predicts the variant to be pathogenic (0.933). The current evidence allows a classification of the variant as “likely pathogenic” (ACMG criteria: PM1, PM5, PM2_supporting, PM3_supporting).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.4
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.65		Loss of stability (P = 0.0465)
MVP		0.96
MPC		0.50
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.88
gMVP		0.84
Mutation Taster		=26/74	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: rs72554620; hg19: chr8-65517310;