7-99672916-T-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 1182 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: Likely_benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291829.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	NM_000777.5	MANE Select	c.219-237A>G		intron	N/A	NP_000768.1
	CYP3A5	NM_001291830.2		c.189-237A>G		intron	N/A	NP_001278759.1
	CYP3A5	NM_001291829.2		c.-253-1A>G		splice_acceptor intron	N/A	NP_001278758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	ENST00000222982.8	TSL:1 MANE Select	c.219-237A>G		intron	N/A	ENSP00000222982.4
	CYP3A5	ENST00000463364.5	TSL:1	n.289-1A>G		splice_acceptor intron	N/A
	CYP3A5	ENST00000466061.5	TSL:1	n.319-1A>G		splice_acceptor intron	N/A

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

African (AFR) AF: 0.271 AC: 6957 AN: 25670

American (AMR) AF: 0.792 AC: 10806 AN: 13638

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 14502 AN: 15650

East Asian (EAS) AF: 0.740 AC: 20631 AN: 27884

South Asian (SAS) AF: 0.731 AC: 29718 AN: 40630

European-Finnish (FIN) AF: 0.929 AC: 19339 AN: 20810

Middle Eastern (MID) AF: 0.905 AC: 3127 AN: 3454

European-Non Finnish (NFE) AF: 0.933 AC: 894134 AN: 958280

Other (OTH) AF: 0.863 AC: 40420 AN: 46834

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

African (AFR) AF: 0.305 AC: 12619 AN: 41412

American (AMR) AF: 0.779 AC: 11907 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3184 AN: 3470

East Asian (EAS) AF: 0.723 AC: 3739 AN: 5168

South Asian (SAS) AF: 0.700 AC: 3373 AN: 4822

European-Finnish (FIN) AF: 0.935 AC: 9898 AN: 10590

Middle Eastern (MID) AF: 0.895 AC: 263 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63345 AN: 68034

Other (OTH) AF: 0.772 AC: 1627 AN: 2108

Alfa AF: 0.837 Hom.: 129402

Bravo AF: 0.701

ClinVar

ClinVar submissions as Germline

Significance: association; drug response; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Hypertension, salt-sensitive essential, susceptibility to (1)
-	-	-	refractory myasthenia gravis (1)
-	-	-	Tacrolimus response (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.9
PhyloP100		0.033

Splicing

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

Other links and lift over

dbSNP: rs776746; hg19: chr7-99270539;