Genetic Variant NM_178134.3:c.1367A>G (chr1-47117783-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_178134.3(CYP4Z1):c.1367A>G(p.His456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP4Z1
NM_178134.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

Variant links:

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]

CYP4Z1 links:

CYP4A22-AS1 (HGNC:43715): (CYP4A22 antisense RNA 1)

CYP4A22-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25542676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4Z1	NM_178134.3 link	c.1367A>G	p.His456Arg	missense_variant	Exon 12 of 12	ENST00000334194.4	NP_835235.1	Q86W10
CYP4Z1	XM_024453856.2 link	c.1253A>G	p.His418Arg	missense_variant	Exon 13 of 13		XP_024309624.1
CYP4A22-AS1	NR_189276.1 link	n.1115-19363T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP4Z1	ENST00000334194.4 link	c.1367A>G	p.His456Arg	missense_variant	Exon 12 of 12	1	NM_178134.3	ENSP00000334246.3	Q86W10
CYP4Z1	ENST00000471598.1 link	n.256A>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
CYP4A22-AS1	ENST00000444042.2 link	n.397-20606T>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461040

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726814

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1367A>G (p.H456R) alteration is located in exon 12 (coding exon 12) of the CYP4Z1 gene. This alteration results from a A to G substitution at nucleotide position 1367, causing the histidine (H) at amino acid position 456 to be replaced by an arginine (R). 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

0.14

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0031

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.44

M_CAP

Benign

0.0045

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.17

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.0

REVEL

Benign

0.13

Sift

Benign

0.044

Sift4G

Benign

0.097

Polyphen

0.68

Vest4

0.13

MutPred

0.56

Loss of catalytic residue at F457 (P = 0.1131);

MVP

0.58

MPC

0.21

ClinPred

0.72

GERP RS

2.2

Varity_R

0.11

gMVP

0.42

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over