NM_000765.5:c.1057T>A

Variant names:

• chr7-99709231-A-T
• rs141574193
• NM_000765.5:c.1057T>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000765.5(CYP3A7):​c.1057T>A​(p.Leu353Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000817 in 1,613,914 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: CYP3A7 NM_000765.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00798133).
• BP6: Variant 7-99709231-A-T is Benign according to our data. Variant chr7-99709231-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2372750.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A7	NM_000765.5	c.1057T>A	p.Leu353Met	missense_variant	Exon 11 of 13	ENST00000336374.4	NP_000756.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A7	ENST00000336374.4	c.1057T>A	p.Leu353Met	missense_variant	Exon 11 of 13	1	NM_000765.5	ENSP00000337450.2
CYP3A7-CYP3A51P	ENST00000620220.6	c.1057T>A	p.Leu353Met	missense_variant	Exon 11 of 13	1		ENSP00000479282.3
CYP3A7-CYP3A51P	ENST00000611620.4	c.1057T>A	p.Leu353Met	missense_variant	Exon 11 of 15	5		ENSP00000480571.1
CYP3A7	ENST00000477357.5	n.1396T>A		non_coding_transcript_exon_variant	Exon 8 of 10	2

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152230 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000650 AC: 163 AN: 250814 AF XY: 0.000649

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.00103

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000819 AC: 1197 AN: 1461566 Hom.: 1 Cov.: 32 AF XY: 0.000838 AC XY: 609 AN XY: 727078

African (AFR) AF: 0.000299 AC: 10 AN: 33466

American (AMR) AF: 0.000448 AC: 20 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39646

South Asian (SAS) AF: 0.000556 AC: 48 AN: 86256

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53392

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5762

European-Non Finnish (NFE) AF: 0.000915 AC: 1017 AN: 1111884

Other (OTH) AF: 0.000944 AC: 57 AN: 60366

GnomAD4 genome AF: 0.000794 AC: 121 AN: 152348 Hom.: 1 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74498

African (AFR) AF: 0.000120 AC: 5 AN: 41582

American (AMR) AF: 0.00209 AC: 32 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000752

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000783 AC: 95

EpiCase AF: 0.00142

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 18, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.63
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0080	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	.;N;.
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	2.5	.;N;.
REVEL	Benign	0.094
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.20
MVP		0.29
MPC		0.12
ClinPred		0.0025	T
GERP RS		2.3
Varity_R		0.18
gMVP		0.62
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs141574193; hg19: chr7-99306854;