7-99734460-C-T

Variant names:

• chr7-99734460-C-T
• rs2687133
• NM_000765.5:c.71+563G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000765.5(CYP3A7):​c.71+563G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.774 in 152,044 control chromosomes in the GnomAD database, including 48,781 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 0.77 (48781 hom., cov: 31)
• Consequence: CYP3A7 NM_000765.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.56
• Publications: 9 publications found

Genes affected

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]

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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000765.5. 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.71+563G>A		intron	N/A	NP_000756.3	P24462-1
	CYP3A7-CYP3A51P	NM_001256497.3		c.71+563G>A		intron	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.71+563G>A		intron	N/A	ENSP00000337450.2	P24462-1
	CYP3A7-CYP3A51P	ENST00000620220.6	TSL:1	c.71+563G>A		intron	N/A	ENSP00000479282.3	A0A087WV96
	CYP3A7-CYP3A51P	ENST00000611620.4	TSL:5	c.71+563G>A		intron	N/A	ENSP00000480571.1

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117668 AN: 151926 Hom.: 48767 Cov.: 31

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.942

Gnomad AMR AF: 0.801

Gnomad ASJ AF: 0.930

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.677

Gnomad FIN AF: 0.947

Gnomad MID AF: 0.804

Gnomad NFE AF: 0.932

Gnomad OTH AF: 0.802

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

GnomAD4 genome AF: 0.774 AC: 117723 AN: 152044 Hom.: 48781 Cov.: 31 AF XY: 0.775 AC XY: 57597 AN XY: 74342

African (AFR) AF: 0.461 AC: 19077 AN: 41392

American (AMR) AF: 0.801 AC: 12243 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.930 AC: 3226 AN: 3470

East Asian (EAS) AF: 0.718 AC: 3707 AN: 5164

South Asian (SAS) AF: 0.678 AC: 3254 AN: 4802

European-Finnish (FIN) AF: 0.947 AC: 10045 AN: 10608

Middle Eastern (MID) AF: 0.816 AC: 240 AN: 294

European-Non Finnish (NFE) AF: 0.932 AC: 63381 AN: 68014

Other (OTH) AF: 0.802 AC: 1691 AN: 2108

Alfa AF: 0.848 Hom.: 7077

Bravo AF: 0.753

Asia WGS AF: 0.667 AC: 2322 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.10
DANN	Benign	0.14
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2687133; hg19: chr7-99332083;