rs4646487

Variant names:

• chr1-46813503-C-T
• rs4646487
• NM_001099772.2:c.517C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001099772.2(CYP4B1):​c.517C>T​(p.Arg173Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,613,946 control chromosomes in the GnomAD database, including 17,209 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1851 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15358 hom.)
• Consequence: CYP4B1 NM_001099772.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.973
• Publications: 53 publications found

Genes affected

CYP4B1 (HGNC:2644): (cytochrome P450 family 4 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 protein localizes to the endoplasmic reticulum. In rodents, the homologous protein has been shown to metabolize certain carcinogens; however, the specific function of the human protein has not been determined. Multiple transcript variants have been found for this gene. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005343884).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4B1	NM_001099772.2	c.517C>T	p.Arg173Trp	missense_variant	Exon 5 of 12	ENST00000371923.9	NP_001093242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4B1	ENST00000371923.9	c.517C>T	p.Arg173Trp	missense_variant	Exon 5 of 12	1	NM_001099772.2	ENSP00000360991.4

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22708 AN: 152094 Hom.: 1850 Cov.: 33

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.256

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.128

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.149 AC: 37391 AN: 251174 AF XY: 0.155

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.198

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.139 AC: 202812 AN: 1461734 Hom.: 15358 Cov.: 33 AF XY: 0.142 AC XY: 103471 AN XY: 727176

African (AFR) AF: 0.193 AC: 6463 AN: 33478

American (AMR) AF: 0.127 AC: 5677 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2646 AN: 26136

East Asian (EAS) AF: 0.183 AC: 7256 AN: 39698

South Asian (SAS) AF: 0.264 AC: 22739 AN: 86252

European-Finnish (FIN) AF: 0.112 AC: 5960 AN: 53360

Middle Eastern (MID) AF: 0.160 AC: 923 AN: 5766

European-Non Finnish (NFE) AF: 0.128 AC: 142641 AN: 1111930

Other (OTH) AF: 0.141 AC: 8507 AN: 60394

GnomAD4 genome AF: 0.149 AC: 22728 AN: 152212 Hom.: 1851 Cov.: 33 AF XY: 0.150 AC XY: 11189 AN XY: 74394

African (AFR) AF: 0.190 AC: 7870 AN: 41506

American (AMR) AF: 0.128 AC: 1959 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 347 AN: 3472

East Asian (EAS) AF: 0.193 AC: 995 AN: 5160

South Asian (SAS) AF: 0.258 AC: 1244 AN: 4824

European-Finnish (FIN) AF: 0.112 AC: 1186 AN: 10612

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8699 AN: 68020

Other (OTH) AF: 0.133 AC: 280 AN: 2112

Alfa AF: 0.136 Hom.: 7057

Bravo AF: 0.149

TwinsUK AF: 0.135 AC: 500

ALSPAC AF: 0.127 AC: 491

ESP6500AA AF: 0.186 AC: 821

ESP6500EA AF: 0.129 AC: 1111

ExAC AF: 0.150 AC: 18184

Asia WGS AF: 0.210 AC: 731 AN: 3478

EpiCase AF: 0.130

EpiControl AF: 0.127

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;.;T;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.85	D;T;T;T;.;D
MetaRNN	Benign	0.0053	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;M;M;.;.;.
PhyloP100		0.97
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	.;N;N;N;.;N
REVEL	Benign	0.12
Sift	Uncertain	0.010	.;D;D;D;.;D
Sift4G	Uncertain	0.020	.;D;D;D;D;T
Polyphen		0.81, 0.84, 1.0	.;P;P;D;.;.
Vest4		0.18, 0.17, 0.12, 0.18
MPC		0.34
ClinPred		0.013	T
GERP RS		0.78
Varity_R		0.074
gMVP		0.28
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4646487; hg19: chr1-47279175; COSMIC: COSV54721701; COSMIC: COSV54721701;