rs8192874

chr8-58496814-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000780.4(CYP7A1):c.698A>G(p.Asn233Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,614,188 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (10 hom.)
• Consequence: CYP7A1 NM_000780.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006983012).
• BP6: Variant 8-58496814-T-C is Benign according to our data. Variant chr8-58496814-T-C is described in ClinVar as [Benign]. Clinvar id is 1584599.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr8-58496814-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000519 (759/1461892) while in subpopulation EAS AF= 0.0179 (710/39700). AF 95% confidence interval is 0.0168. There are 10 homozygotes in gnomad4_exome. There are 355 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP7A1	NM_000780.4	c.698A>G	p.Asn233Ser	missense_variant	3/6	ENST00000301645.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP7A1	ENST00000301645.4	c.698A>G	p.Asn233Ser	missense_variant	3/6	1	NM_000780.4	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 251494 Hom.: 4 AF XY: 0.000949 AC XY: 129 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0130

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000519 AC: 759 AN: 1461892 Hom.: 10 Cov.: 33 AF XY: 0.000488 AC XY: 355 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0179

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000414 Hom.: 1

Bravo AF: 0.000544

ExAC AF: 0.00105 AC: 127

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.11
Dann	Benign	0.12
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	0.83	T
Polyphen		0.0	B
Vest4		0.026
MVP		0.58
MPC		0.070
ClinPred		0.016	T
GERP RS		0.67
Varity_R		0.083
gMVP		0.080

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

Publications

LitVar

Other links and lift over

dbSNP: rs8192874; hg19: chr8-59409373; COSMIC: COSV56964009;