chr8-64616281-C-T

Variant names:

• chr8-64616281-C-T
• rs587777221
• NM_004820.5:c.260G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004820.5(CYP7B1):​c.260G>A​(p.Gly87Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000286 in 1,397,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G87V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CYP7B1 NM_004820.5 missense, splice_region
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.94
• Publications: 4 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.260G>A	p.Gly87Glu	missense splice_region	Exon 3 of 6	NP_004811.1	O75881
	CYP7B1	NM_001324112.2		c.260G>A	p.Gly87Glu	missense splice_region	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.260G>A	p.Gly87Glu	missense splice_region	Exon 3 of 6	ENSP00000310721.3	O75881
	CYP7B1	ENST00000864436.1		c.413G>A	p.Gly138Glu	missense splice_region	Exon 5 of 8	ENSP00000534495.1
	CYP7B1	ENST00000864435.1		c.260G>A	p.Gly87Glu	missense splice_region	Exon 4 of 7	ENSP00000534494.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000969 AC: 2 AN: 206416 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1397858 Hom.: 0 Cov.: 25 AF XY: 0.00000144 AC XY: 1 AN XY: 696126

African (AFR) AF: 0.00 AC: 0 AN: 31484

American (AMR) AF: 0.00 AC: 0 AN: 41510

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25268

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.0000372 AC: 3 AN: 80606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4470

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068224

Other (OTH) AF: 0.00 AC: 0 AN: 57884

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.90		Gain of catalytic residue at G87 (P = 0.1378)
MVP		0.93
MPC		0.50
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.87
gMVP		0.87
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
SpliceAI score (max)		0.030		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: rs587777221; hg19: chr8-65528838;