8-58494425-T-C

Variant names:

• chr8-58494425-T-C
• rs3747809
• NM_000780.4:c.1039+81A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000780.4(CYP7A1):​c.1039+81A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,455,608 control chromosomes in the GnomAD database, including 54 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 0.0014 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (48 hom.)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.459
• Publications: 2 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=-0.9).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00143 (218/152272) while in subpopulation EAS AF = 0.0364 (189/5186). AF 95% confidence interval is 0.0322. There are 6 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 SD gene

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.1039+81A>G		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.1039+81A>G		intron	N/A	ENSP00000301645.3

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 219 AN: 152154 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0364

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00167 AC: 2172 AN: 1303336 Hom.: 48 AF XY: 0.00169 AC XY: 1111 AN XY: 656180

African (AFR) AF: 0.0000331 AC: 1 AN: 30208

American (AMR) AF: 0.000136 AC: 6 AN: 44272

Ashkenazi Jewish (ASJ) AF: 0.0000400 AC: 1 AN: 25026

East Asian (EAS) AF: 0.0487 AC: 1888 AN: 38746

South Asian (SAS) AF: 0.00148 AC: 122 AN: 82488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51378

Middle Eastern (MID) AF: 0.000545 AC: 3 AN: 5500

European-Non Finnish (NFE) AF: 0.0000783 AC: 76 AN: 970654

Other (OTH) AF: 0.00136 AC: 75 AN: 55064

GnomAD4 genome AF: 0.00143 AC: 218 AN: 152272 Hom.: 6 Cov.: 32 AF XY: 0.00188 AC XY: 140 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0364 AC: 189 AN: 5186

South Asian (SAS) AF: 0.00396 AC: 19 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000300 Hom.: 1

Bravo AF: 0.00162

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.46
DANN	Benign	0.40
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism

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: rs3747809; hg19: chr8-59406984;