rs2257401

Positions:

• chr7-99709062-G-C

Variant summary

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

The NM_000765.5(CYP3A7):​c.1226C>G​(p.Thr409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,613,714 control chromosomes in the GnomAD database, including 24,610 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (7206 hom., cov: 32)
  • Exomes 𝑓: 0.12 (17404 hom.)
• Consequence: CYP3A7 NM_000765.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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 (MetaRNN=0.0073284805).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.1226C>G	p.Thr409Arg	missense_variant	11/13	ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.1226C>G	p.Thr409Arg	missense_variant	11/13	1	NM_000765.5	ENSP00000337450.2
CYP3A7-CYP3A51P	ENST00000620220.6	c.1226C>G	p.Thr409Arg	missense_variant	11/13	1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.1226C>G	p.Thr409Arg	missense_variant	11/15	5		ENSP00000480571.1
CYP3A7	ENST00000477357.5	n.1565C>G		non_coding_transcript_exon_variant	8/10	2

Frequencies

GnomAD3 genomes AF: 0.237 AC: 35953 AN: 151910 Hom.: 7189 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.0990

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.0872

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.120 AC: 175418 AN: 1461686 Hom.: 17404 Cov.: 33 AF XY: 0.123 AC XY: 89734 AN XY: 727144

Gnomad4 AFR exome AF: 0.555

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.0948

Gnomad4 EAS exome AF: 0.261

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.0752

Gnomad4 NFE exome AF: 0.0843

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.237 AC: 36015 AN: 152028 Hom.: 7206 Cov.: 32 AF XY: 0.236 AC XY: 17562 AN XY: 74318

Gnomad4 AFR AF: 0.535

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.0990

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.325

Gnomad4 FIN AF: 0.0678

Gnomad4 NFE AF: 0.0872

Gnomad4 OTH AF: 0.216

Alfa AF: 0.126 Hom.: 728

Bravo AF: 0.258

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_noAF	Benign	-0.57
CADD	Benign	20
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0073	T;T;T
Sift4G	Uncertain	0.011	D;D;D
Vest4		0.31
gMVP		0.71

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2257401; hg19: chr7-99306685;