chr1-47084879-C-T

Variant names:

• chr1-47084879-C-T
• rs147199588
• NM_178134.3:c.673C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_178134.3(CYP4Z1):​c.673C>T​(p.Arg225Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,535,014 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R225S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CYP4Z1 NM_178134.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.862
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07671225).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178134.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4Z1	NM_178134.3	MANE Select	c.673C>T	p.Arg225Cys	missense	Exon 6 of 12	NP_835235.1	Q86W10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4Z1	ENST00000334194.4	TSL:1 MANE Select	c.673C>T	p.Arg225Cys	missense	Exon 6 of 12	ENSP00000334246.3	Q86W10

Frequencies

GnomAD3 genomes AF: 0.000956 AC: 142 AN: 148574 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00149

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00150

GnomAD2 exomes AF: 0.000647 AC: 128 AN: 197820 AF XY: 0.000618

Gnomad AFR exome AF: 0.000459

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.000642

GnomAD4 exome AF: 0.00135 AC: 1870 AN: 1386322 Hom.: 2 Cov.: 28 AF XY: 0.00130 AC XY: 886 AN XY: 683298

African (AFR) AF: 0.000291 AC: 9 AN: 30962

American (AMR) AF: 0.00116 AC: 38 AN: 32894

Ashkenazi Jewish (ASJ) AF: 0.0000466 AC: 1 AN: 21446

East Asian (EAS) AF: 0.00 AC: 0 AN: 39014

South Asian (SAS) AF: 0.000178 AC: 13 AN: 73104

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50932

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5384

European-Non Finnish (NFE) AF: 0.00161 AC: 1733 AN: 1075378

Other (OTH) AF: 0.00133 AC: 76 AN: 57208

GnomAD4 genome AF: 0.000962 AC: 143 AN: 148692 Hom.: 0 Cov.: 26 AF XY: 0.000912 AC XY: 66 AN XY: 72340

African (AFR) AF: 0.000373 AC: 15 AN: 40192

American (AMR) AF: 0.00148 AC: 22 AN: 14836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4964

South Asian (SAS) AF: 0.000222 AC: 1 AN: 4506

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00151 AC: 102 AN: 67438

Other (OTH) AF: 0.00148 AC: 3 AN: 2026

Alfa AF: 0.000401 Hom.: 0

Bravo AF: 0.00112

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00175 AC: 15

ExAC AF: 0.000594 AC: 72

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.86
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Benign	0.22
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.23
MVP		0.56
MPC		2.7
ClinPred		0.14	T
GERP RS		1.3
Varity_R		0.68
gMVP		0.68
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs147199588; hg19: chr1-47550551;