8-58499507-T-G

Variant names:

• chr8-58499507-T-G
• rs8192870
• NM_000780.4:c.80+512A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000780.4(CYP7A1):​c.80+512A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.72 in 152,172 control chromosomes in the GnomAD database, including 39,987 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (39987 hom., cov: 34)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.414
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.842 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.80+512A>C		intron	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.80+512A>C		intron	N/A	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.719 AC: 109387 AN: 152054 Hom.: 39925 Cov.: 34

Gnomad AFR AF: 0.849

Gnomad AMI AF: 0.670

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.693

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.675

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.725

Gnomad NFE AF: 0.651

Gnomad OTH AF: 0.712

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

GnomAD4 genome AF: 0.720 AC: 109514 AN: 152172 Hom.: 39987 Cov.: 34 AF XY: 0.716 AC XY: 53291 AN XY: 74382

African (AFR) AF: 0.849 AC: 35298 AN: 41554

American (AMR) AF: 0.762 AC: 11661 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 2405 AN: 3468

East Asian (EAS) AF: 0.783 AC: 4057 AN: 5184

South Asian (SAS) AF: 0.675 AC: 3254 AN: 4824

European-Finnish (FIN) AF: 0.590 AC: 6247 AN: 10594

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.651 AC: 44257 AN: 67938

Other (OTH) AF: 0.716 AC: 1510 AN: 2108

Alfa AF: 0.673 Hom.: 57346

Bravo AF: 0.740

Asia WGS AF: 0.742 AC: 2580 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.59
PhyloP100		0.41
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: rs8192870; hg19: chr8-59412066;