chr8-58492376-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000780.4(CYP7A1):c.1192C>G(p.Pro398Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00433 in 1,613,906 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0045 ( 21 hom. )

Consequence

CYP7A1
NM_000780.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.85

Publications

11 publications found

Variant links:

Genes affected

CYP7A1 (HGNC:2651): (cytochrome P450 family 7 subfamily A 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 in the liver, which converts cholesterol to bile acids. This reaction is the rate limiting step and the major site of regulation of bile acid synthesis, which is the primary mechanism for the removal of cholesterol from the body. Polymorphisms in the promoter of this gene are associated with defects in bile acid synthesis. [provided by RefSeq, Feb 2010]

CYP7A1 Gene-Disease associations (from GenCC):

hypercholesterolemia due to cholesterol 7alpha-hydroxylase deficiency
Inheritance: SD Classification: SUPPORTIVE Submitted by: Orphanet

CYP7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03252712).

BP6

Variant 8-58492376-G-C is Benign according to our data. Variant chr8-58492376-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 288450.

BS2

High Homozygotes in GnomAdExome4 at 21 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP7A1	NM_000780.4 link	c.1192C>G	p.Pro398Ala	missense_variant	Exon 5 of 6	ENST00000301645.4	NP_000771.2	P22680

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP7A1	ENST00000301645.4 link	c.1192C>G	p.Pro398Ala	missense_variant	Exon 5 of 6	1	NM_000780.4	ENSP00000301645.3		P22680

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

441

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000869

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00478

Gnomad FIN

AF:

0.00746

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00390

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00341

AC:

858

AN:

251488

AF XY:

0.00361

show subpopulations

Gnomad AFR exome

AF:

0.00141

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00633

Gnomad NFE exome

AF:

0.00433

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00448

AC:

6544

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00445

AC XY:

3234

AN XY:

727158

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33478

American (AMR)

AF:

0.000783

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00333

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00445

AC:

384

AN:

86248

European-Finnish (FIN)

AF:

0.00543

AC:

290

AN:

53416

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00492

AC:

5466

AN:

1111850

Other (OTH)

AF:

0.00411

AC:

248

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

336

673

1009

1346

1682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.00290

AC:

442

AN:

152202

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

41542

American (AMR)

AF:

0.00131

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00499

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00746

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00390

AC:

265

AN:

68006

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00370

Hom.:

Bravo

AF:

0.00259

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.00325

AC:

394

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP7A1: BS2 -

Sep 30, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Jun 03, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CYP7A1-related disorder

Benign:1

Apr 14, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.031

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.91

MutationAssessor

Pathogenic

3.0

PhyloP100

7.9

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.6

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.62

MVP

0.85

MPC

0.13

ClinPred

0.073

GERP RS

5.2

Varity_R

0.87

gMVP

0.78

Mutation Taster

=74/26

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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