rs776746

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-99672916-T-A
• chr7-99672916-T-C
• chr7-99672916-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001291829.2(CYP3A5):​c.-253-1A>T variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000173 in 1,153,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CYP3A5 NM_001291829.2 splice_acceptor, intron
• Scores: Splicing: ADA: 0.00003782
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 0 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_pathogenic. The variant received 6 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 4.4, offset of -18, new splice context is: taaccataatctctttaaAGagc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	NM_000777.5	MANE Select	c.219-237A>T		intron	N/A	NP_000768.1	P20815-1
	CYP3A5	NM_001291830.2		c.189-237A>T		intron	N/A	NP_001278759.1
	CYP3A5	NM_001291829.2		c.-253-1A>T		splice_acceptor 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.219-237A>T		intron	N/A	ENSP00000222982.4	P20815-1
	CYP3A5	ENST00000463364.5	TSL:1	n.289-1A>T		splice_acceptor intron	N/A
	CYP3A5	ENST00000466061.5	TSL:1	n.319-1A>T		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000173 AC: 2 AN: 1153306 Hom.: 0 Cov.: 25 AF XY: 0.00000181 AC XY: 1 AN XY: 551370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25690

American (AMR) AF: 0.00 AC: 0 AN: 13656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15668

East Asian (EAS) AF: 0.00 AC: 0 AN: 27954

South Asian (SAS) AF: 0.00 AC: 0 AN: 40686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3458

European-Non Finnish (NFE) AF: 0.00000209 AC: 2 AN: 958496

Other (OTH) AF: 0.00 AC: 0 AN: 46874

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
PhyloP100		0.033

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000038
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.010		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: rs776746; hg19: chr7-99270539;