8-58491017-C-T

Variant names:

• chr8-58491017-C-T
• rs8192879
• NM_000780.4:c.*458G>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.*458G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 156,314 control chromosomes in the GnomAD database, including 9,965 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 0.35 (9649 hom., cov: 32)
  • Exomes 𝑓: 0.36 (316 hom.)
• Consequence: CYP7A1 NM_000780.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 22 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.455 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.*458G>A		3_prime_UTR	Exon 6 of 6	NP_000771.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7A1	ENST00000301645.4	TSL:1 MANE Select	c.*458G>A		3_prime_UTR	Exon 6 of 6	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52689 AN: 151900 Hom.: 9642 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.370

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.365 AC: 1568 AN: 4296 Hom.: 316 Cov.: 0 AF XY: 0.368 AC XY: 806 AN XY: 2190

African (AFR) AF: 0.212 AC: 28 AN: 132

American (AMR) AF: 0.487 AC: 147 AN: 302

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 49 AN: 166

East Asian (EAS) AF: 0.341 AC: 71 AN: 208

South Asian (SAS) AF: 0.342 AC: 41 AN: 120

European-Finnish (FIN) AF: 0.362 AC: 68 AN: 188

Middle Eastern (MID) AF: 0.300 AC: 3 AN: 10

European-Non Finnish (NFE) AF: 0.366 AC: 1080 AN: 2952

Other (OTH) AF: 0.372 AC: 81 AN: 218

GnomAD4 genome AF: 0.347 AC: 52726 AN: 152018 Hom.: 9649 Cov.: 32 AF XY: 0.349 AC XY: 25897 AN XY: 74302

African (AFR) AF: 0.234 AC: 9706 AN: 41450

American (AMR) AF: 0.464 AC: 7083 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1255 AN: 3470

East Asian (EAS) AF: 0.307 AC: 1589 AN: 5170

South Asian (SAS) AF: 0.395 AC: 1906 AN: 4824

European-Finnish (FIN) AF: 0.374 AC: 3955 AN: 10562

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.383 AC: 26033 AN: 67948

Other (OTH) AF: 0.357 AC: 754 AN: 2114

Alfa AF: 0.371 Hom.: 48676

Bravo AF: 0.348

Asia WGS AF: 0.372 AC: 1292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.92
DANN	Benign	0.42
PhyloP100		-0.20
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: rs8192879; hg19: chr8-59403576;