rs35637877

Variant names:

• chr3-42874748-G-A
• rs35637877
• NM_004391.3:c.1069C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-42874748-G-A
• chr3-42874748-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004391.3(CYP8B1):​c.1069C>T​(p.Leu357Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00371 in 1,614,040 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L357L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.020 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (106 hom.)
• Consequence: CYP8B1 NM_004391.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.182
• Publications: 7 publications found

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]

ENSG00000290317 (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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009719402).
• BP6: Variant 3-42874748-G-A is Benign according to our data. Variant chr3-42874748-G-A is described in ClinVar as Benign. ClinVar VariationId is 780380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0681 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004391.3. 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
	CYP8B1	NM_004391.3	MANE Select	c.1069C>T	p.Leu357Phe	missense	Exon 1 of 1	NP_004382.2	Q9UNU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP8B1	ENST00000316161.6	TSL:6 MANE Select	c.1069C>T	p.Leu357Phe	missense	Exon 1 of 1	ENSP00000318867.4	Q9UNU6
	CYP8B1	ENST00000437102.1	TSL:1	c.1069C>T	p.Leu357Phe	missense	Exon 1 of 2	ENSP00000404499.1	C9JFR9
	ENSG00000290317	ENST00000426937.5	TSL:3	c.-163-34045G>A		intron	N/A	ENSP00000413859.1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3058 AN: 152050 Hom.: 109 Cov.: 32

Gnomad AFR AF: 0.0703

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00688

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0139

GnomAD2 exomes AF: 0.00501 AC: 1259 AN: 251368 AF XY: 0.00352

Gnomad AFR exome AF: 0.0703

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00200 AC: 2919 AN: 1461872 Hom.: 106 Cov.: 32 AF XY: 0.00169 AC XY: 1228 AN XY: 727242

African (AFR) AF: 0.0733 AC: 2453 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111992

Other (OTH) AF: 0.00440 AC: 266 AN: 60396

GnomAD4 genome AF: 0.0201 AC: 3062 AN: 152168 Hom.: 109 Cov.: 32 AF XY: 0.0189 AC XY: 1409 AN XY: 74396

African (AFR) AF: 0.0702 AC: 2913 AN: 41490

American (AMR) AF: 0.00687 AC: 105 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68008

Other (OTH) AF: 0.0137 AC: 29 AN: 2110

Alfa AF: 0.00782 Hom.: 90

Bravo AF: 0.0232

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0645 AC: 284

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00640 AC: 777

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.035
DANN	Benign	0.49
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0097	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.18
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.085
Sift	Benign	0.74	T
Sift4G	Benign	0.71	T
Polyphen		0.022	B
Vest4		0.12
MVP		0.030
MPC		0.32
ClinPred		0.0043	T
GERP RS		-9.3
Varity_R		0.045
gMVP		0.50
Mutation Taster		=99/1	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: rs35637877; hg19: chr3-42916240;