rs776746

Variant names:

• chr7-99672916-T-C
• rs776746
• NM_000777.5:c.219-237A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_001291829.2(CYP3A5):​c.-253-1A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.882 in 1,304,936 control chromosomes in the GnomAD database, including 522,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association,drug response,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.73 (45998 hom., cov: 31)
  • Exomes 𝑓: 0.90 (476110 hom.)
• Consequence: CYP3A5 NM_001291829.2 splice_acceptor, intron
• Clinical Significance: association; drug response; risk factor no assertion criteria provided O:4
• Conservation: PhyloP100: 0.0330

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:21961): (zinc finger and SCAN domain containing 25) This gene encodes a protein that bears some similarity to zinc finger proteins, which are involved in DNA binding and protein-protein interactions. Multiple alternatively spliced transcript variants have been identified, but the full-length nature for most of them has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11282051 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7, offset of 0 (no position change), new splice context is: agagctcttttgtctttcAGtat. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.219-237A>G		intron_variant	Intron 3 of 12	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.219-237A>G		intron_variant	Intron 3 of 12	1	NM_000777.5	ENSP00000222982.4

Frequencies

GnomAD3 genomes AF: 0.729 AC: 110783 AN: 151968 Hom.: 45993 Cov.: 31

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.779

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.935

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.770

GnomAD4 exome AF: 0.902 AC: 1039634 AN: 1152850 Hom.: 476110 Cov.: 25 AF XY: 0.901 AC XY: 496393 AN XY: 551124

Gnomad4 AFR exome AF: 0.271

Gnomad4 AMR exome AF: 0.792

Gnomad4 ASJ exome AF: 0.927

Gnomad4 EAS exome AF: 0.740

Gnomad4 SAS exome AF: 0.731

Gnomad4 FIN exome AF: 0.929

Gnomad4 NFE exome AF: 0.933

Gnomad4 OTH exome AF: 0.863

GnomAD4 genome AF: 0.729 AC: 110806 AN: 152086 Hom.: 45998 Cov.: 31 AF XY: 0.730 AC XY: 54257 AN XY: 74364

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.779

Gnomad4 ASJ AF: 0.918

Gnomad4 EAS AF: 0.723

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.935

Gnomad4 NFE AF: 0.931

Gnomad4 OTH AF: 0.772

Alfa AF: 0.887 Hom.: 94215

Bravo AF: 0.701

ClinVar

Significance: association; drug response; risk factor

Submissions summary: Other:4

Revision: no assertion criteria provided

Submissions by phenotype

Tacrolimus response Other:2

drug response, no assertion criteria provided	research	Pharmacy Department, Siriraj Hospital, Mahidol University	Apr 15, 2022	The risk of immunological complications is generally highest during the early period after kidney transplantation. Adequate immunosuppression is crucial during this critical period since lower tacrolimus exposure at approximately one week post-kidney transplantation has been associated with subsequently higher rates of acute rejection [Undre 1999, Borobia 2009, O’Seaghdha 2009, Richards 2014]. The very low dosage of 60 mg/day diltiazem affects tacrolimus exposure in CYP3A5 expressers and may reduce tacrolimus dosage requirement in CYP3A5 expressers to achieve the same exposure of the drug in nonexpressers during the first week after kidney transplantation. -
drug response, no assertion criteria provided	research	Pharmacy Practice Department, Chulalongkorn University	Dec 31, 2021	Fluctuation of tacrolimus exposure in an individual transplant recipient has been recognized as a tool for identifying patients at risk of poor outcomes (Shuker 2016, Gonzales 2020). No evidence of impact of the CYP3A5 genetic polymorphisms on tacrolimus intra-patient variability of dose-adjusted trough concentrations during 6 to 12 months after kidney transplantation was determined. However, significant influence of the polymorphisms on tacrolimus exposure was found when comparing CYP3A5 expressers with nonexpressers at months 6, 9, and 12 after transplantation, with large effect. -

refractory myasthenia gravis Other:1

association, no assertion criteria provided

clinical testing

Department of Neurology lab, Tongji Hospital, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology

Mar 23, 2022

Genetic polymorphisms of CYP3A5 influence the blood trough concentration and efficacy of tacrolimus for myasthenia gravis patients. CYP3A5 rs776746 were predictive factors for refractory myasthenia gravis. -

Hypertension, salt-sensitive essential, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs776746; hg19: chr7-99270539;