rs2687075

Positions:

• chr7-99717363-A-G
• chr7-99717363-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000765.5(CYP3A7):​c.433-98T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.869 in 1,603,298 control chromosomes in the GnomAD database, including 615,846 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 0.76 (47136 hom., cov: 33)
  • Exomes 𝑓: 0.88 (568710 hom.)
• Consequence: CYP3A7 NM_000765.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143

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]

CYP3A7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.907 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.433-98T>C		intron_variant		ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.433-98T>C		intron_variant		1	NM_000765.5	ENSP00000337450.2
CYP3A7-CYP3A51P	ENST00000620220.6	c.433-98T>C		intron_variant		1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.433-98T>C		intron_variant		5		ENSP00000480571.1
CYP3A7	ENST00000477357.5	n.772-98T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115869 AN: 152074 Hom.: 47122 Cov.: 33

Gnomad AFR AF: 0.461

Gnomad AMI AF: 0.930

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.901

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.932

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.913

Gnomad OTH AF: 0.782

GnomAD4 exome AF: 0.880 AC: 1276936 AN: 1451106 Hom.: 568710 Cov.: 30 AF XY: 0.877 AC XY: 633368 AN XY: 722576

Gnomad4 AFR exome AF: 0.443

Gnomad4 AMR exome AF: 0.774

Gnomad4 ASJ exome AF: 0.905

Gnomad4 EAS exome AF: 0.738

Gnomad4 SAS exome AF: 0.694

Gnomad4 FIN exome AF: 0.925

Gnomad4 NFE exome AF: 0.916

Gnomad4 OTH exome AF: 0.852

GnomAD4 genome AF: 0.762 AC: 115924 AN: 152192 Hom.: 47136 Cov.: 33 AF XY: 0.762 AC XY: 56723 AN XY: 74416

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.901

Gnomad4 EAS AF: 0.718

Gnomad4 SAS AF: 0.675

Gnomad4 FIN AF: 0.932

Gnomad4 NFE AF: 0.913

Gnomad4 OTH AF: 0.783

Alfa AF: 0.883 Hom.: 73727

Bravo AF: 0.741

Asia WGS AF: 0.672 AC: 2338 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.3
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs2687075; hg19: chr7-99314986;