8-58497880-C-T

Variant names:

• chr8-58497880-C-T
• rs1457043
• NM_000780.4:c.321+349G>A

Variant summary

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

The NM_000780.4(CYP7A1):​c.321+349G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 152,006 control chromosomes in the GnomAD database, including 22,541 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 0.54 (22541 hom., cov: 32)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.821
• Publications: 16 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.645 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP7A1	NM_000780.4	c.321+349G>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+349G>A		intron_variant	Intron 2 of 5	1	NM_000780.4	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81781 AN: 151888 Hom.: 22520 Cov.: 32

Gnomad AFR AF: 0.438

Gnomad AMI AF: 0.605

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.486

Gnomad MID AF: 0.636

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.538 AC: 81835 AN: 152006 Hom.: 22541 Cov.: 32 AF XY: 0.535 AC XY: 39725 AN XY: 74284

African (AFR) AF: 0.437 AC: 18104 AN: 41422

American (AMR) AF: 0.656 AC: 10018 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2228 AN: 3470

East Asian (EAS) AF: 0.432 AC: 2232 AN: 5172

South Asian (SAS) AF: 0.506 AC: 2439 AN: 4822

European-Finnish (FIN) AF: 0.486 AC: 5127 AN: 10556

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.585 AC: 39754 AN: 67966

Other (OTH) AF: 0.564 AC: 1194 AN: 2116

Alfa AF: 0.572 Hom.: 78484

Bravo AF: 0.547

Asia WGS AF: 0.515 AC: 1791 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.20
DANN	Benign	0.71
PhyloP100		-0.82
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: rs1457043; hg19: chr8-59410439;