rs4646446

Variant names:

• chr7-99677460-C-T
• rs4646446
• NM_000777.5:c.72-1252G>A

Variant summary

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

The NM_000777.5(CYP3A5):​c.72-1252G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0579 in 152,272 control chromosomes in the GnomAD database, including 529 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 0.058 (529 hom., cov: 32)
• Consequence: CYP3A5 NM_000777.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.64
• Publications: 7 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000777.5. 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
	CYP3A5	NM_000777.5	MANE Select	c.72-1252G>A		intron	N/A	NP_000768.1	P20815-1
	CYP3A5	NM_001291830.2		c.-219-884G>A		intron	N/A	NP_001278759.1
	CYP3A5	NM_001291829.2		c.-768-884G>A		intron	N/A	NP_001278758.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	ENST00000222982.8	TSL:1 MANE Select	c.72-1252G>A		intron	N/A	ENSP00000222982.4	P20815-1
	CYP3A5	ENST00000463364.5	TSL:1	n.142-1252G>A		intron	N/A
	CYP3A5	ENST00000466061.5	TSL:1	n.172-1252G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0579 AC: 8814 AN: 152152 Hom.: 532 Cov.: 32

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0904

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.0149

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0626

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

GnomAD4 genome AF: 0.0579 AC: 8817 AN: 152272 Hom.: 529 Cov.: 32 AF XY: 0.0638 AC XY: 4749 AN XY: 74442

African (AFR) AF: 0.0722 AC: 3000 AN: 41534

American (AMR) AF: 0.0906 AC: 1386 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3470

East Asian (EAS) AF: 0.250 AC: 1295 AN: 5176

South Asian (SAS) AF: 0.247 AC: 1191 AN: 4822

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: 1507 AN: 68032

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0343 Hom.: 276

Bravo AF: 0.0606

Asia WGS AF: 0.236 AC: 818 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.67
DANN	Benign	0.56
PhyloP100		-1.6
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: rs4646446; hg19: chr7-99275083;