8-64798532-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004820.5(CYP7B1):c.56T>C(p.Leu19Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,499,110 control chromosomes in the GnomAD database, including 645 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L19R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.039 ( 376 hom., cov: 33)

Exomes 𝑓: 0.0035 ( 269 hom. )

Consequence

CYP7B1
NM_004820.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0950

Publications

5 publications found

Variant links:

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

CYP7B1 links:

ENSG00000287998 (HGNC:):

ENSG00000287998 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017033815).

BP6

Variant 8-64798532-A-G is Benign according to our data. Variant chr8-64798532-A-G is described in ClinVar as Benign. ClinVar VariationId is 193293.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CYP7B1	NM_004820.5 link	c.56T>C	p.Leu19Pro	missense_variant	Exon 1 of 6	ENST00000310193.4	NP_004811.1
CYP7B1	NM_001324112.2 link	c.56T>C	p.Leu19Pro	missense_variant	Exon 1 of 7		NP_001311041.1
LOC105375879	XR_928992.3 link	n.-249A>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CYP7B1	ENST00000310193.4 link	c.56T>C	p.Leu19Pro	missense_variant	Exon 1 of 6	1	NM_004820.5	ENSP00000310721.3
ENSG00000287998	ENST00000833571.1 link	n.69A>G		non_coding_transcript_exon_variant	Exon 1 of 2
ENSG00000287998	ENST00000833563.1 link	n.-82A>G		upstream_gene_variant
ENSG00000287998	ENST00000833570.1 link	n.-162A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.0386

AC:

5872

AN:

152134

Hom.:

377

Cov.:

show subpopulations

Gnomad AFR

AF:

0.134

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0149

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.00302

AC:

289

AN:

95666

AF XY:

0.00230

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.00510

Gnomad ASJ exome

AF:

0.000145

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000613

Gnomad OTH exome

AF:

0.00413

GnomAD4 exome

AF:

0.00352

AC:

4739

AN:

1346868

Hom.:

269

Cov.:

AF XY:

0.00303

AC XY:

2011

AN XY:

664370

show subpopulations

African (AFR)

AF:

0.136

AC:

3691

AN:

27150

American (AMR)

AF:

0.00688

AC:

212

AN:

30836

Ashkenazi Jewish (ASJ)

AF:

0.000167

AC:

AN:

23900

East Asian (EAS)

AF:

0.00

AC:

AN:

31094

South Asian (SAS)

AF:

0.000410

AC:

AN:

75554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33270

Middle Eastern (MID)

AF:

0.00857

AC:

AN:

3968

European-Non Finnish (NFE)

AF:

0.000284

AC:

303

AN:

1065032

Other (OTH)

AF:

0.00828

AC:

464

AN:

56064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

228

456

685

913

1141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0386

AC:

5877

AN:

152242

Hom.:

376

Cov.:

AF XY:

0.0372

AC XY:

2772

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.134

AC:

5552

AN:

41522

American (AMR)

AF:

0.0149

AC:

228

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68014

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

277

554

830

1107

1384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0213

Hom.:

Bravo

AF:

0.0435

ESP6500AA

AF:

0.0376

AC:

104

ESP6500EA

AF:

0.000343

AC:

ExAC

AF:

0.00298

AC:

191

Asia WGS

AF:

0.00636

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 14, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 12, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Nov 12, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 5A

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.42

CADD

Benign

8.4

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.23

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.28

MetaRNN

Benign

0.0017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.095

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.65

REVEL

Benign

0.20

Sift

Uncertain

0.016

Sift4G

Benign

0.088

Polyphen

0.0010

Vest4

0.27

MVP

0.42

MPC

0.14

ClinPred

0.0069

GERP RS

-0.71

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.11

gMVP

0.84

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over