rs45494802

Variant names:

• chr7-99735377-A-T
• rs45494802
• XR_007059988.1:n.1429-1315A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The XR_927402.3(ZSCAN25):​n.1456-1315A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0247 in 151,524 control chromosomes in the GnomAD database, including 74 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 0.025 (74 hom., cov: 31)
• Consequence: ZSCAN25 XR_927402.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.102
• Publications: 5 publications found

Genes affected

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]

CYP3A7 (HGNC:2640): (cytochrome P450 family 3 subfamily A member 7) This gene encodes a member of the cytochrome P450 superfamily of enzymes, which participate in drug metabolism and the synthesis of cholesterol, steroids and other lipids. This enzyme hydroxylates testosterone and dehydroepiandrosterone 3-sulphate, which is involved in the formation of estriol during pregnancy. This gene is part of a cluster of related genes on chromosome 7q21.1. Naturally-occurring readthrough transcription occurs between this gene and the downstream CYP3A51P pseudogene and is represented by GeneID:100861540. [provided by RefSeq, Jan 2015]

CYP3A7-CYP3A51P (HGNC:51504): (CYP3A7-CYP3A51P readthrough) This locus represents readthrough transcription between the neighboring CYP3A7 (cytochrome P450, family 3, subfamily A, polypeptide 7) and CYP3A51P (cytochrome P450, family 3, subfamily A, polypeptide 51, pseudogene) genes, which are members of the CYP3A gene cluster on chromosome 7. The downstream pseudogene is not known to be independently transcribed. The readthrough transcript includes CYP3A7 exons 1-13 and exons 2 and 13 of the pseudogene. It encodes a CYP3A isoform with a novel C-terminus. This isoform is only expressed in alleles containing a T nucleotide at the -6 position of a splice acceptor in the pseudogene, which enables correct splicing of the upstream CYP3A7 exons to the pseudogene exons. It should be noted that the reference genome sequence represents the CYP3A7_39256 T->A allele, and thus this haplotype is unlikely to produce the readthrough transcript. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS2: High Homozygotes in GnomAd4 at 74 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000336374.4. 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
	CYP3A7	NM_000765.5	MANE Select	c.-284T>A		upstream_gene	N/A	NP_000756.3	P24462-1
	CYP3A7-CYP3A51P	NM_001256497.3		c.-284T>A		upstream_gene	N/A	NP_001243426.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A7	ENST00000336374.4	TSL:1 MANE Select	c.-284T>A		upstream_gene	N/A	ENSP00000337450.2	P24462-1
	CYP3A7	ENST00000467776.1	TSL:3	n.-181T>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3739 AN: 151408 Hom.: 73 Cov.: 31

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0278

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.0458

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.0332

Gnomad OTH AF: 0.0279

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

GnomAD4 genome AF: 0.0247 AC: 3740 AN: 151524 Hom.: 74 Cov.: 31 AF XY: 0.0246 AC XY: 1822 AN XY: 74038

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

African (AFR) AF: 0.00914 AC: 379 AN: 41460

American (AMR) AF: 0.0267 AC: 406 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0278 AC: 96 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.0125 AC: 60 AN: 4810

European-Finnish (FIN) AF: 0.0458 AC: 482 AN: 10520

Middle Eastern (MID) AF: 0.0207 AC: 6 AN: 290

European-Non Finnish (NFE) AF: 0.0332 AC: 2246 AN: 67572

Other (OTH) AF: 0.0276 AC: 58 AN: 2100

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0298 Hom.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	4.8
DANN	Benign	0.42
PhyloP100		0.10
PromoterAI		-0.031	Neutral

Splicing

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

Other links and lift over

dbSNP: rs45494802; hg19: chr7-99333000;