rs4646450

Positions:

• chr7-99668695-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000777.5(CYP3A5):​c.319-1630C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 152,178 control chromosomes in the GnomAD database, including 17,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency: Genomes: 𝑓 0.38 (17458 hom., cov: 33)
• Consequence: CYP3A5 NM_000777.5 intron
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.539

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A5	NM_000777.5	c.319-1630C>T		intron_variant		ENST00000222982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A5	ENST00000222982.8	c.319-1630C>T		intron_variant		1	NM_000777.5	P1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 57092 AN: 152060 Hom.: 17393 Cov.: 33

Gnomad AFR AF: 0.842

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.335

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.376 AC: 57223 AN: 152178 Hom.: 17458 Cov.: 33 AF XY: 0.376 AC XY: 27962 AN XY: 74402

Gnomad4 AFR AF: 0.843

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.285

Gnomad4 SAS AF: 0.373

Gnomad4 FIN AF: 0.180

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.340

Alfa AF: 0.190 Hom.: 8448

Bravo AF: 0.404

Asia WGS AF: 0.411 AC: 1429 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

appendicular lean mass relative to body height Other:1

association, no assertion criteria provided

reference population

Human Population Biology Research Unit, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University

-

X12063 is an endogenous molecule, one of 360 metabolites identified by Metabolon Inc. using ultrahigh performance liquid chromatography and mass spectrometry. X12063 circulating levels were highly significantly associated with skeletal muscle mass, as assessed by appendicular lean mass relative to body height (p=2.85E-42). GWAS demonstrated that X12063 was associated with 7q22.1 genomic region with top p-value 4.987E-50 for SNP rs4646450:G>A. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.46
DANN	Benign	0.48

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

LitVar

Other links and lift over

dbSNP: rs4646450; hg19: chr7-99266318;