XR_007059988.1:n.1429-1367T>G

Variant names:

• chr7-99735325-T-G
• rs45446698
• XR_007059988.1:n.1429-1367T>G

Variant summary

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

The XR_007059988.1(ZSCAN25):​n.1429-1367T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 558,348 control chromosomes in the GnomAD database, including 303 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 0.026 (82 hom., cov: 31)
  • Exomes 𝑓: 0.029 (221 hom.)
• Consequence: ZSCAN25 XR_007059988.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.614
• Publications: 41 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=-0.93).
• BS2: High Homozygotes in GnomAd4 at 82 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.-232A>C		upstream_gene_variant		ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.-232A>C		upstream_gene_variant		1	NM_000765.5	ENSP00000337450.2
CYP3A7-CYP3A51P	ENST00000620220.6	c.-232A>C		upstream_gene_variant		1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.-232A>C		upstream_gene_variant		5		ENSP00000480571.1
CYP3A7	ENST00000467776.1	n.-129A>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0263 AC: 3991 AN: 151804 Hom.: 81 Cov.: 31

Gnomad AFR AF: 0.00984

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.0289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0472

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0355

Gnomad OTH AF: 0.0307

GnomAD4 exome AF: 0.0288 AC: 11704 AN: 406426 Hom.: 221 AF XY: 0.0283 AC XY: 6167 AN XY: 218018

African (AFR) AF: 0.00980 AC: 113 AN: 11536

American (AMR) AF: 0.0228 AC: 453 AN: 19874

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 300 AN: 12378

East Asian (EAS) AF: 0.000154 AC: 4 AN: 25952

South Asian (SAS) AF: 0.0164 AC: 765 AN: 46736

European-Finnish (FIN) AF: 0.0458 AC: 1081 AN: 23578

Middle Eastern (MID) AF: 0.0180 AC: 32 AN: 1780

European-Non Finnish (NFE) AF: 0.0343 AC: 8296 AN: 241532

Other (OTH) AF: 0.0286 AC: 660 AN: 23060

GnomAD4 genome AF: 0.0263 AC: 3992 AN: 151922 Hom.: 82 Cov.: 31 AF XY: 0.0264 AC XY: 1961 AN XY: 74262

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

African (AFR) AF: 0.00983 AC: 408 AN: 41504

American (AMR) AF: 0.0281 AC: 429 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 100 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4804

European-Finnish (FIN) AF: 0.0472 AC: 498 AN: 10550

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2411 AN: 67858

Other (OTH) AF: 0.0304 AC: 64 AN: 2108

⚠️ 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: 0.0329 Hom.: 57

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.6
DANN	Benign	0.67
PhyloP100		-0.61
PromoterAI		-0.0066	Neutral

Splicing

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

Other links and lift over

dbSNP: rs45446698; hg19: chr7-99332948;