rs4646453

Variant names:

• chr7-99662739-C-A
• rs4646453
• NM_000777.5:c.865+77G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000777.5(CYP3A5):​c.865+77G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,376,960 control chromosomes in the GnomAD database, including 4,651 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (549 hom., cov: 32)
  • Exomes 𝑓: 0.047 (4102 hom.)
• Consequence: CYP3A5 NM_000777.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.241 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.865+77G>T		intron_variant	Intron 9 of 12	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.865+77G>T		intron_variant	Intron 9 of 12	1	NM_000777.5	ENSP00000222982.4

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9063 AN: 152122 Hom.: 552 Cov.: 32

Gnomad AFR AF: 0.0781

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0903

Gnomad ASJ AF: 0.0386

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0640

GnomAD4 exome AF: 0.0469 AC: 57388 AN: 1224720 Hom.: 4102 AF XY: 0.0516 AC XY: 31991 AN XY: 620112

African (AFR) AF: 0.0773 AC: 2171 AN: 28102

American (AMR) AF: 0.108 AC: 4454 AN: 41072

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 741 AN: 23336

East Asian (EAS) AF: 0.238 AC: 9110 AN: 38222

South Asian (SAS) AF: 0.220 AC: 17493 AN: 79648

European-Finnish (FIN) AF: 0.0148 AC: 771 AN: 52040

Middle Eastern (MID) AF: 0.0338 AC: 176 AN: 5204

European-Non Finnish (NFE) AF: 0.0216 AC: 19592 AN: 904972

Other (OTH) AF: 0.0553 AC: 2880 AN: 52124

GnomAD4 genome AF: 0.0596 AC: 9071 AN: 152240 Hom.: 549 Cov.: 32 AF XY: 0.0653 AC XY: 4859 AN XY: 74430

African (AFR) AF: 0.0783 AC: 3250 AN: 41528

American (AMR) AF: 0.0905 AC: 1384 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0386 AC: 134 AN: 3470

East Asian (EAS) AF: 0.252 AC: 1303 AN: 5172

South Asian (SAS) AF: 0.245 AC: 1180 AN: 4824

European-Finnish (FIN) AF: 0.0149 AC: 158 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0222 AC: 1512 AN: 68020

Other (OTH) AF: 0.0633 AC: 134 AN: 2116

Alfa AF: 0.0477 Hom.: 240

Bravo AF: 0.0625

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.58
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

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: rs4646453; hg19: chr7-99260362; COSMIC: COSV56119062; COSMIC: COSV56119062;