rs28451617

Variant names:

• chr7-99735142-C-T
• rs28451617
• NM_000765.5:c.-49G>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.-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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 8 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 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.-49G>A		5_prime_UTR	Exon 1 of 13	NP_000756.3
	CYP3A7-CYP3A51P	NM_001256497.3		c.-49G>A		5_prime_UTR	Exon 1 of 15	NP_001243426.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A7	ENST00000336374.4	TSL:1 MANE Select	c.-49G>A		5_prime_UTR	Exon 1 of 13	ENSP00000337450.2
	CYP3A7	ENST00000467776.1	TSL:3	n.55G>A		non_coding_transcript_exon	Exon 1 of 2
	CYP3A7-CYP3A51P	ENST00000620220.6	TSL:1	c.-49G>A		upstream_gene	N/A	ENSP00000479282.3

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

GnomAD2 exomes AF: 0.00924 AC: 2299 AN: 248752 AF XY: 0.00671

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 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

African (AFR) AF: 0.111 AC: 3711 AN: 33404

American (AMR) AF: 0.0131 AC: 583 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.000329 AC: 13 AN: 39512

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86142

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53174

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5750

European-Non Finnish (NFE) AF: 0.000691 AC: 767 AN: 1109838

Other (OTH) AF: 0.00850 AC: 512 AN: 60246

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

African (AFR) AF: 0.104 AC: 4328 AN: 41506

American (AMR) AF: 0.0224 AC: 343 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68014

Other (OTH) AF: 0.0260 AC: 55 AN: 2112

Alfa AF: 0.0134 Hom.: 239

Bravo AF: 0.0357

Asia WGS AF: 0.00953 AC: 33 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.2
DANN	Benign	0.52
PhyloP100		-0.46
PromoterAI		-0.041	Neutral

Splicing

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

Other links and lift over

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