rs4646487

chr1-46813503-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005343884).
• BP6: Variant 1-46813503-C-T is Benign according to our data. Variant chr1-46813503-C-T is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
CYP4B1	NM_001099772.2	c.517C>T	p.Arg173Trp	missense_variant	5/12	ENST00000371923.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4B1	ENST00000371923.9	c.517C>T	p.Arg173Trp	missense_variant	5/12	1	NM_001099772.2	A1

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

GnomAD3 exomes AF: 0.149 AC: 37391 AN: 251174 Hom.: 3102 AF XY: 0.155 AC XY: 21089 AN XY: 135738

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 SAS exome AF: 0.262

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

Gnomad4 AFR exome AF: 0.193

Gnomad4 AMR exome AF: 0.127

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.183

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.112

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.141

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

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0999

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.258

Gnomad4 FIN AF: 0.112

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.133

Alfa AF: 0.134 Hom.: 3428

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
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4646487; hg19: chr1-47279175; COSMIC: COSV54721701; COSMIC: COSV54721701;