rs142708991

chr8-58492376-G-Cchr8-58492376-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03252712).
• BS2: High Homozygotes in GnomAdExome at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP7A1	NM_000780.4	c.1192C>G	p.Pro398Ala	missense_variant	5/6	ENST00000301645.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP7A1	ENST00000301645.4	c.1192C>G	p.Pro398Ala	missense_variant	5/6	1	NM_000780.4	P1

Frequencies

GnomAD3 genomes AF: 0.00290 AC: 441 AN: 152084 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.00341 AC: 858 AN: 251488 Hom.: 4 AF XY: 0.00361 AC XY: 490 AN XY: 135920

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 SAS exome AF: 0.00408

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.: 21 Cov.: 31 AF XY: 0.00445 AC XY: 3234 AN XY: 727158

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00333

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00445

Gnomad4 FIN exome AF: 0.00543

Gnomad4 NFE exome AF: 0.00492

Gnomad4 OTH exome AF: 0.00411

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74392

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00746

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00370 Hom.: 3

Bravo AF: 0.00259

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00325 AC: 394

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 09, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CYP7A1: BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 03, 2016

- -

CYP7A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 14, 2021

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	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.62
MVP		0.85
MPC		0.13
ClinPred		0.073	T
GERP RS		5.2
Varity_R		0.87
gMVP		0.78

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: rs142708991; hg19: chr8-59404935;