chr1-46799208-A-C

Variant names:

• chr1-46799208-A-C
• NM_001099772.2:c.127A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001319162.2(CYP4B1):​c.-176A>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP4B1 NM_001319162.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.348

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043699056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4B1	NM_001099772.2	c.127A>C	p.Met43Leu	missense_variant	Exon 1 of 12	ENST00000371923.9	NP_001093242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4B1	ENST00000371923.9	c.127A>C	p.Met43Leu	missense_variant	Exon 1 of 12	1	NM_001099772.2	ENSP00000360991.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127A>C (p.M43L) alteration is located in exon 1 (coding exon 1) of the CYP4B1 gene. This alteration results from a A to C substitution at nucleotide position 127, causing the methionine (M) at amino acid position 43 to be replaced by a leucine (L). 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	0.13
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.062
DANN	Benign	0.40
DEOGEN2	Benign	0.0022	T;.;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.60	T;T;T;T;.
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.044	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.41	.;N;N;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.56	.;N;N;N;.
REVEL	Benign	0.088
Sift	Benign	1.0	.;T;T;T;.
Sift4G	Benign	1.0	.;T;T;T;T
Polyphen		0.0	.;B;B;B;.
Vest4		0.18, 0.14, 0.26, 0.19
MutPred		0.37		Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);Loss of disorder (P = 0.1231);
MVP		0.28
MPC		0.083
ClinPred		0.039	T
GERP RS		-5.1
Varity_R		0.070
gMVP		0.26

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: chr1-47264880;