rs1457042

Variant names:

• chr8-58498073-C-T
• rs1457042
• NM_000780.4:c.321+156G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000780.4(CYP7A1):​c.321+156G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 152,000 control chromosomes in the GnomAD database, including 9,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.35 (9821 hom., cov: 33)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.158
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-58498073-C-T is Benign according to our data. Variant chr8-58498073-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP7A1	NM_000780.4	c.321+156G>A		intron_variant	Intron 2 of 5	ENST00000301645.4	NP_000771.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP7A1	ENST00000301645.4	c.321+156G>A		intron_variant	Intron 2 of 5	1	NM_000780.4	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.349 AC: 53008 AN: 151880 Hom.: 9809 Cov.: 33

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.352

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.379

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.359

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.349 AC: 53052 AN: 152000 Hom.: 9821 Cov.: 33 AF XY: 0.351 AC XY: 26085 AN XY: 74304

African (AFR) AF: 0.238 AC: 9843 AN: 41444

American (AMR) AF: 0.504 AC: 7707 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3470

East Asian (EAS) AF: 0.352 AC: 1822 AN: 5170

South Asian (SAS) AF: 0.377 AC: 1816 AN: 4820

European-Finnish (FIN) AF: 0.366 AC: 3857 AN: 10542

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25620 AN: 67956

Other (OTH) AF: 0.360 AC: 760 AN: 2110

Alfa AF: 0.347 Hom.: 1232

Bravo AF: 0.355

Asia WGS AF: 0.378 AC: 1315 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.46
PhyloP100		-0.16
Mutation Taster		=100/0	polymorphism (auto)

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: rs1457042; hg19: chr8-59410632;