7-99707970-T-C

Variant names:

• chr7-99707970-T-C
• rs1321570575
• NM_000765.5:c.1258A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000765.5(CYP3A7):​c.1258A>G​(p.Ser420Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,548 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYP3A7 NM_000765.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.1258A>G	p.Ser420Gly	missense_variant	Exon 12 of 13	ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.1258A>G	p.Ser420Gly	missense_variant	Exon 12 of 13	1	NM_000765.5	ENSP00000337450.2
CYP3A7-CYP3A51P	ENST00000620220.6	c.1258A>G	p.Ser420Gly	missense_variant	Exon 12 of 13	1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.1258A>G	p.Ser420Gly	missense_variant	Exon 12 of 15	5		ENSP00000480571.1
CYP3A7	ENST00000477357.5	n.1597A>G		non_coding_transcript_exon_variant	Exon 9 of 10	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251036 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135658

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461548 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727078

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1258A>G (p.S420G) alteration is located in exon 12 (coding exon 12) of the CYP3A7 gene. This alteration results from a A to G substitution at nucleotide position 1258, causing the serine (S) at amino acid position 420 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.5	.;H;.
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	.;D;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.010	.;D;.
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.21	.;B;.
Vest4		0.28
MutPred		0.53		Loss of stability (P = 0.017);Loss of stability (P = 0.017);Loss of stability (P = 0.017);
MVP		0.72
MPC		0.20
ClinPred		0.74	D
GERP RS		3.7
Varity_R		0.45
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1321570575; hg19: chr7-99305593;