chr3-42874613-C-T

Position:

• chr3-42874613-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004391.3(CYP8B1):​c.1204G>A​(p.Val402Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00841 in 1,614,040 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (73 hom.)
• Consequence: CYP8B1 NM_004391.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.873

Genes affected

CYP8B1 (HGNC:2653): (cytochrome P450 family 8 subfamily B 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 conversion of 7 alpha-hydroxy-4-cholesten-3-one into 7-alpha,12-alpha-dihydroxy-4-cholesten-3-one. The balance between these two steroids determines the relative amounts of cholic acid and chenodeoxycholic acid both of which are secreted in the bile and affect the solubility of cholesterol. This gene is unique among the cytochrome P450 genes in that it is intronless. [provided by RefSeq, Jul 2008]

(HGNC:):

ACKR2 (HGNC:1565): (atypical chemokine receptor 2) This gene encodes a beta chemokine receptor, which is predicted to be a seven transmembrane protein similar to G protein-coupled receptors. Chemokines and their receptor-mediated signal transduction are critical for the recruitment of effector immune cells to the inflammation site. This gene is expressed in a range of tissues and hemopoietic cells. The expression of this receptor in lymphatic endothelial cells and overexpression in vascular tumors suggested its function in chemokine-driven recirculation of leukocytes and possible chemokine effects on the development and growth of vascular tumors. This receptor appears to bind the majority of beta-chemokine family members; however, its specific function remains unknown. This gene is mapped to chromosome 3p21.3, a region that includes a cluster of chemokine receptor genes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011722803).
• BP6: Variant 3-42874613-C-T is Benign according to our data. Variant chr3-42874613-C-T is described in ClinVar as [Benign]. Clinvar id is 769272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP8B1	NM_004391.3	c.1204G>A	p.Val402Ile	missense_variant	1/1	ENST00000316161.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP8B1	ENST00000316161.6	c.1204G>A	p.Val402Ile	missense_variant	1/1		NM_004391.3	P1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1022 AN: 152032 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00965

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00592 AC: 1488 AN: 251486 Hom.: 12 AF XY: 0.00578 AC XY: 786 AN XY: 135918

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0146

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00859 AC: 12557 AN: 1461890 Hom.: 73 Cov.: 32 AF XY: 0.00840 AC XY: 6109 AN XY: 727248

Gnomad4 AFR exome AF: 0.00128

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.00704

GnomAD4 genome AF: 0.00671 AC: 1021 AN: 152150 Hom.: 4 Cov.: 32 AF XY: 0.00698 AC XY: 519 AN XY: 74354

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00687

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00963

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00799 Hom.: 9

Bravo AF: 0.00541

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00586 AC: 712

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00752

EpiControl AF: 0.00771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.14
DANN	Benign	0.77
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.44	T;T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.034
Sift	Benign	0.21	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.012	B;B
Vest4		0.058
MVP		0.014
MPC		0.089
ClinPred		0.0032	T
GERP RS		-7.0
Varity_R		0.026
gMVP		0.39

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: rs112066175; hg19: chr3-42916105;