1-47082343-T-C

Position:

• chr1-47082343-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_178134.3(CYP4Z1):​c.374T>C​(p.Leu125Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CYP4Z1 NM_178134.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

Genes affected

CYP4Z1 (HGNC:20583): (cytochrome P450 family 4 subfamily Z 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 gene is part of a cluster of cytochrome P450 genes on chromosome 1p33. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4Z1	NM_178134.3	c.374T>C	p.Leu125Pro	missense_variant	4/12	ENST00000334194.4	NP_835235.1
CYP4Z1	XM_024453856.2	c.260T>C	p.Leu87Pro	missense_variant	5/13		XP_024309624.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4Z1	ENST00000334194.4	c.374T>C	p.Leu125Pro	missense_variant	4/12	1	NM_178134.3	ENSP00000334246.3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 29

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

Jul 09, 2024

The c.374T>C (p.L125P) alteration is located in exon 4 (coding exon 4) of the CYP4Z1 gene. This alteration results from a T to C substitution at nucleotide position 374, causing the leucine (L) at amino acid position 125 to be replaced by a proline (P). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.021	T
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.085	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.93		Gain of disorder (P = 0.0565);
MVP		0.68
MPC		3.0
ClinPred		0.98	D
GERP RS		2.3
Varity_R		0.96
gMVP		0.86

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: chr1-47548015;