rs2297810

chr1-46815187-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001099772.2(CYP4B1):c.996G>A(p.Met332Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,611,698 control chromosomes in the GnomAD database, including 25,331 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (5290 hom., cov: 32)
  • Exomes 𝑓: 0.16 (20041 hom.)
• Consequence: CYP4B1 NM_001099772.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.09

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=0.0028523207).
• BP6: Variant 1-46815187-G-A is Benign according to our data. Variant chr1-46815187-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4B1	NM_001099772.2	c.996G>A	p.Met332Ile	missense_variant	8/12	ENST00000371923.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4B1	ENST00000371923.9	c.996G>A	p.Met332Ile	missense_variant	8/12	1	NM_001099772.2	A1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35295 AN: 152024 Hom.: 5251 Cov.: 32

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.218

GnomAD3 exomes AF: 0.186 AC: 46498 AN: 249498 Hom.: 5074 AF XY: 0.179 AC XY: 24120 AN XY: 134770

Gnomad AFR exome AF: 0.427

Gnomad AMR exome AF: 0.218

Gnomad ASJ exome AF: 0.138

Gnomad EAS exome AF: 0.261

Gnomad SAS exome AF: 0.174

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.156 AC: 227614 AN: 1459556 Hom.: 20041 Cov.: 33 AF XY: 0.156 AC XY: 113064 AN XY: 726076

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.288

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.233 AC: 35376 AN: 152142 Hom.: 5290 Cov.: 32 AF XY: 0.232 AC XY: 17249 AN XY: 74374

Gnomad4 AFR AF: 0.418

Gnomad4 AMR AF: 0.230

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.214

Alfa AF: 0.161 Hom.: 6112

Bravo AF: 0.246

TwinsUK AF: 0.136 AC: 506

ALSPAC AF: 0.130 AC: 501

ESP6500AA AF: 0.413 AC: 1819

ESP6500EA AF: 0.147 AC: 1265

ExAC AF: 0.191 AC: 23243

Asia WGS AF: 0.246 AC: 856 AN: 3478

EpiCase AF: 0.143

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	20
Dann	Uncertain	0.99
Eigen	Benign	-0.042
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0029	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	0.00086	P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.28
Sift	Benign	0.051	T;T;D
Sift4G	Uncertain	0.039	D;D;D
Polyphen		0.032	B;B;B
Vest4		0.38
MutPred		0.23		.;Loss of catalytic residue at M331 (P = 0.0825);.;
MPC		0.11
ClinPred		0.051	T
GERP RS		4.0
Varity_R		0.43
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2297810; hg19: chr1-47280859; COSMIC: COSV54721270; COSMIC: COSV54721270;