8-58500365-G-T

Variant names:

• chr8-58500365-G-T
• rs3808607
• NM_000780.4:c.-267C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000780.4(CYP7A1):​c.-267C>A variant causes a upstream gene change. The variant allele was found at a frequency of 0.568 in 407,118 control chromosomes in the GnomAD database, including 66,983 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23418 hom., cov: 32)
  • Exomes 𝑓: 0.58 (43565 hom.)
• Consequence: CYP7A1 NM_000780.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25
• Publications: 116 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 8-58500365-G-T is Benign according to our data. Variant chr8-58500365-G-T is described in ClinVar as Benign. ClinVar VariationId is 1229509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.652 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000780.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7A1	NM_000780.4	MANE Select	c.-267C>A		upstream_gene	N/A	NP_000771.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7A1	ENST00000301645.4	TSL:1 MANE Select	c.-267C>A		upstream_gene	N/A	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83111 AN: 151748 Hom.: 23399 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.604

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.537

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.601

Gnomad OTH AF: 0.567

GnomAD4 exome AF: 0.581 AC: 148203 AN: 255252 Hom.: 43565 AF XY: 0.578 AC XY: 78587 AN XY: 135926

African (AFR) AF: 0.411 AC: 3298 AN: 8032

American (AMR) AF: 0.683 AC: 7236 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.644 AC: 4944 AN: 7672

East Asian (EAS) AF: 0.519 AC: 8799 AN: 16966

South Asian (SAS) AF: 0.551 AC: 17512 AN: 31756

European-Finnish (FIN) AF: 0.519 AC: 6406 AN: 12350

Middle Eastern (MID) AF: 0.631 AC: 685 AN: 1086

European-Non Finnish (NFE) AF: 0.596 AC: 90768 AN: 152272

Other (OTH) AF: 0.589 AC: 8555 AN: 14516

GnomAD4 genome AF: 0.548 AC: 83159 AN: 151866 Hom.: 23418 Cov.: 32 AF XY: 0.545 AC XY: 40441 AN XY: 74202

African (AFR) AF: 0.419 AC: 17355 AN: 41426

American (AMR) AF: 0.663 AC: 10114 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2266 AN: 3466

East Asian (EAS) AF: 0.538 AC: 2789 AN: 5186

South Asian (SAS) AF: 0.567 AC: 2739 AN: 4830

European-Finnish (FIN) AF: 0.488 AC: 5141 AN: 10532

Middle Eastern (MID) AF: 0.668 AC: 195 AN: 292

European-Non Finnish (NFE) AF: 0.601 AC: 40801 AN: 67858

Other (OTH) AF: 0.573 AC: 1208 AN: 2110

Alfa AF: 0.586 Hom.: 94553

Bravo AF: 0.555

Asia WGS AF: 0.559 AC: 1945 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15262185, 19850125, 18178499, 18728290, 20884100)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.85
PhyloP100		4.2
PromoterAI		-0.0084	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3808607; hg19: chr8-59412924;