NM_000780.4:c.1216-108T>C

Variant names:

• chr8-58491882-A-G
• rs8192877
• NM_000780.4:c.1216-108T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000780.4(CYP7A1):​c.1216-108T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 904,936 control chromosomes in the GnomAD database, including 8,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1237 hom., cov: 32)
  • Exomes 𝑓: 0.13 (6993 hom.)
• Consequence: CYP7A1 NM_000780.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 10 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-58491882-A-G is Benign according to our data. Variant chr8-58491882-A-G is described in ClinVar as Benign. ClinVar VariationId is 1235467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.151 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7A1	NM_000780.4	MANE Select	c.1216-108T>C		intron	N/A	NP_000771.2	P22680

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP7A1	ENST00000301645.4	TSL:1 MANE Select	c.1216-108T>C		intron	N/A	ENSP00000301645.3	P22680

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18866 AN: 152150 Hom.: 1238 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.0377

Gnomad SAS AF: 0.0841

Gnomad FIN AF: 0.0774

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.130 AC: 97707 AN: 752670 Hom.: 6993 AF XY: 0.129 AC XY: 51296 AN XY: 397202

African (AFR) AF: 0.102 AC: 1862 AN: 18306

American (AMR) AF: 0.0780 AC: 2400 AN: 30780

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3511 AN: 20144

East Asian (EAS) AF: 0.0473 AC: 1645 AN: 34772

South Asian (SAS) AF: 0.0859 AC: 5493 AN: 63916

European-Finnish (FIN) AF: 0.0967 AC: 3603 AN: 37268

Middle Eastern (MID) AF: 0.171 AC: 470 AN: 2752

European-Non Finnish (NFE) AF: 0.145 AC: 73903 AN: 508168

Other (OTH) AF: 0.132 AC: 4820 AN: 36564

GnomAD4 genome AF: 0.124 AC: 18862 AN: 152266 Hom.: 1237 Cov.: 32 AF XY: 0.120 AC XY: 8970 AN XY: 74456

African (AFR) AF: 0.103 AC: 4269 AN: 41574

American (AMR) AF: 0.108 AC: 1644 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 640 AN: 3464

East Asian (EAS) AF: 0.0380 AC: 197 AN: 5186

South Asian (SAS) AF: 0.0842 AC: 406 AN: 4820

European-Finnish (FIN) AF: 0.0774 AC: 821 AN: 10604

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10406 AN: 68020

Other (OTH) AF: 0.139 AC: 293 AN: 2112

Alfa AF: 0.142 Hom.: 2675

Bravo AF: 0.126

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.5
DANN	Benign	0.80
PhyloP100		1.3
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: rs8192877; hg19: chr8-59404441;