rs3215983

chr1-46815074-GAT-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001099772.2(CYP4B1):c.884_885del(p.Asp295GlyfsTer3) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.139 in 1,612,232 control chromosomes in the GnomAD database, including 16,629 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.12 (1398 hom., cov: 30)
  • Exomes 𝑓: 0.14 (15231 hom.)
• Consequence: CYP4B1 NM_001099772.2 frameshift, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.26

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 -10 ACMG points.

• BP6: Variant 1-46815074-GAT-G is Benign according to our data. Variant chr1-46815074-GAT-G is described in ClinVar as [Benign]. Clinvar id is 402584.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-46815074-GAT-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4B1	NM_001099772.2	c.884_885del	p.Asp295GlyfsTer3	frameshift_variant, splice_region_variant	8/12	ENST00000371923.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4B1	ENST00000371923.9	c.884_885del	p.Asp295GlyfsTer3	frameshift_variant, splice_region_variant	8/12	1	NM_001099772.2	A1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18745 AN: 152030 Hom.: 1393 Cov.: 30

Gnomad AFR AF: 0.0520

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.134

GnomAD3 exomes AF: 0.149 AC: 37317 AN: 250554 Hom.: 2955 AF XY: 0.147 AC XY: 19962 AN XY: 135382

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.133

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.140 AC: 204684 AN: 1460084 Hom.: 15231 AF XY: 0.140 AC XY: 102031 AN XY: 726420

Gnomad4 AFR exome AF: 0.0473

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.273

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.136

Gnomad4 OTH exome AF: 0.143

GnomAD4 genome AF: 0.123 AC: 18756 AN: 152148 Hom.: 1398 Cov.: 30 AF XY: 0.126 AC XY: 9389 AN XY: 74380

Gnomad4 AFR AF: 0.0523

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.256

Gnomad4 SAS AF: 0.134

Gnomad4 FIN AF: 0.143

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.130

Alfa AF: 0.135 Hom.: 254

Bravo AF: 0.122

Asia WGS AF: 0.195 AC: 679 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.135

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in 1000Genomes: 381/2178=17.49% -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3215983; hg19: chr1-47280746; COSMIC: COSV54725102; COSMIC: COSV54725102;