rs28451617

Positions:

• chr7-99735142-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000765.5(CYP3A7):​c.-49G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,610,904 control chromosomes in the GnomAD database, including 476 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 0.032 (239 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (237 hom.)
• Consequence: CYP3A7 NM_000765.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 7-99735142-C-T is Benign according to our data. Variant chr7-99735142-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.-49G>A		5_prime_UTR_variant	1/13	ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.-49G>A		5_prime_UTR_variant	1/13	1	NM_000765.5	ENSP00000337450.2
CYP3A7	ENST00000467776.1	n.55G>A		non_coding_transcript_exon_variant	1/2	3
CYP3A7-CYP3A51P	ENST00000620220.6	c.-49G>A		upstream_gene_variant		1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.-49G>A		upstream_gene_variant		5		ENSP00000480571.1

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4766 AN: 152088 Hom.: 231 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.00924 AC: 2299 AN: 248752 Hom.: 99 AF XY: 0.00671 AC XY: 903 AN XY: 134548

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000444

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.000866

Gnomad OTH exome AF: 0.00857

GnomAD4 exome AF: 0.00390 AC: 5683 AN: 1458696 Hom.: 237 Cov.: 30 AF XY: 0.00344 AC XY: 2498 AN XY: 725640

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000329

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.000691

Gnomad4 OTH exome AF: 0.00850

GnomAD4 genome AF: 0.0315 AC: 4797 AN: 152208 Hom.: 239 Cov.: 31 AF XY: 0.0304 AC XY: 2265 AN XY: 74414

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0224

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.00591 Hom.: 57

Bravo AF: 0.0357

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.2
DANN	Benign	0.52

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28451617; hg19: chr7-99332765; COSMIC: COSV60480897;