chr1-46812586-A-T

Position:

• chr1-46812586-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001099772.2(CYP4B1):​c.458A>T​(p.Tyr153Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP4B1 NM_001099772.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.70

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4B1	NM_001099772.2	c.458A>T	p.Tyr153Phe	missense_variant	4/12	ENST00000371923.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4B1	ENST00000371923.9	c.458A>T	p.Tyr153Phe	missense_variant	4/12	1	NM_001099772.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.458A>T (p.Y153F) alteration is located in exon 4 (coding exon 4) of the CYP4B1 gene. This alteration results from a A to T substitution at nucleotide position 458, causing the tyrosine (Y) at amino acid position 153 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T;.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;.
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.83	.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.0	.;D;D;D;.
REVEL	Uncertain	0.53
Sift	Benign	0.054	.;T;T;D;.
Sift4G	Benign	0.11	.;T;T;T;D
Polyphen		0.98, 0.98, 1.0	.;D;D;D;.
Vest4		0.66, 0.68, 0.64, 0.65
MutPred		0.69		Gain of methylation at K151 (P = 0.0424);Gain of methylation at K151 (P = 0.0424);Gain of methylation at K151 (P = 0.0424);.;Gain of methylation at K151 (P = 0.0424);
MVP		0.67
MPC		0.43
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.51
gMVP		0.38

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-47278258;