rs45446698

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The XR_927402.3(ZSCAN25):​n.1456-1367T>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. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.026 (82 hom., cov: 31)
  • Exomes 𝑓: 0.029 (221 hom.)
• Consequence: ZSCAN25 XR_927402.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.614

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-99735325-T-G is Benign according to our data. Variant chr7-99735325-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0263 (3992/151922) while in subpopulation NFE AF= 0.0355 (2411/67858). AF 95% confidence interval is 0.0343. There are 82 homozygotes in gnomad4. There are 1961 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• 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

Gnomad4 AFR exome AF: 0.00980

Gnomad4 AMR exome AF: 0.0228

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.000154

Gnomad4 SAS exome AF: 0.0164

Gnomad4 FIN exome AF: 0.0458

Gnomad4 NFE exome AF: 0.0343

Gnomad4 OTH exome AF: 0.0286

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

Gnomad4 AFR AF: 0.00983

Gnomad4 AMR AF: 0.0281

Gnomad4 ASJ AF: 0.0289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0472

Gnomad4 NFE AF: 0.0355

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.0341 Hom.: 26

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs45446698; hg19: chr7-99332948;