rs28383468

Positions:

• chr7-99676192-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000777.5(CYP3A5):​c.88C>T​(p.His30Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00786 in 1,613,744 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0059 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0081 (59 hom.)
• Consequence: CYP3A5 NM_000777.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60

Genes affected

CYP3A5 (HGNC:2638): (cytochrome P450 family 3 subfamily A member 5) 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. The encoded protein metabolizes drugs as well as the steroid hormones testosterone and progesterone. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Two pseudogenes of this gene have been identified within this cluster on chromosome 7. Expression of this gene is widely variable among populations, and a single nucleotide polymorphism that affects transcript splicing has been associated with susceptibility to hypertensions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ZSCAN25 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004989326).
• BP6: Variant 7-99676192-G-A is Benign according to our data. Variant chr7-99676192-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2657725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 900 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A5	NM_000777.5	c.88C>T	p.His30Tyr	missense_variant	2/13	ENST00000222982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A5	ENST00000222982.8	c.88C>T	p.His30Tyr	missense_variant	2/13	1	NM_000777.5	P1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152198 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00693 AC: 1741 AN: 251308 Hom.: 11 AF XY: 0.00725 AC XY: 985 AN XY: 135824

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00735

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00604

Gnomad FIN exome AF: 0.00370

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00806 AC: 11786 AN: 1461428 Hom.: 59 Cov.: 32 AF XY: 0.00798 AC XY: 5800 AN XY: 727014

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.00712

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00596

Gnomad4 FIN exome AF: 0.00417

Gnomad4 NFE exome AF: 0.00911

Gnomad4 OTH exome AF: 0.00737

GnomAD4 genome AF: 0.00591 AC: 900 AN: 152316 Hom.: 8 Cov.: 31 AF XY: 0.00584 AC XY: 435 AN XY: 74478

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00634

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00941

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00266 Hom.: 4

Bravo AF: 0.00572

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00746 AC: 906

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.0106

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

CYP3A5: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	12
DANN	Benign	0.30
DEOGEN2	Benign	0.0044	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0050	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	N;N;N;N
PROVEAN	Benign	-1.7	N;D
REVEL	Benign	0.071
Sift	Benign	0.55	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;.
Vest4		0.16
MVP		0.16
MPC		0.25
ClinPred		0.0046	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28383468; hg19: chr7-99273815;