7-99709231-A-T

Position:

chr7-99709231-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The ENST00000336374.4(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. 16/21 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
ENST00000336374.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.49

Variant links:

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 links:

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-CYP3A51P links:

CYP3A7 (HGNC:):

CYP3A7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein	UniProt
CYP3A7	NM_000765.5 linkuse as main transcript	c.1057T>A	p.Leu353Met	missense_variant	11/13	ENST00000336374.4	NP_000756.3	P24462-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CYP3A7	ENST00000336374.4 linkuse as main transcript	c.1057T>A	p.Leu353Met	missense_variant	11/13	1	NM_000765.5	ENSP00000337450.2	P24462-1
CYP3A7-CYP3A51P	ENST00000620220.6 linkuse as main transcript	c.1057T>A	p.Leu353Met	missense_variant	11/13	1		ENSP00000479282.3	A0A087WV96
CYP3A7-CYP3A51P	ENST00000611620.4 linkuse as main transcript	c.1057T>A	p.Leu353Met	missense_variant	11/15	5		ENSP00000480571.1
CYP3A7	ENST00000477357.5 linkuse as main transcript	n.1396T>A		non_coding_transcript_exon_variant	8/10	2

Frequencies

GnomAD3 genomes

AF:

0.000801

AC:

122

AN:

152230

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000650

AC:

163

AN:

250814

Hom.:

AF XY:

0.000649

AC XY:

AN XY:

135568

show subpopulations

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 SAS exome

AF:

0.000457

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.:

Cov.:

AF XY:

0.000838

AC XY:

609

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.000450

Gnomad4 NFE exome

AF:

0.000915

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000794

AC:

121

AN:

152348

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00113

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000467

Hom.:

Bravo

AF:

0.000752

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000783

AC:

EpiCase

AF:

0.00142

EpiControl

AF:

0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2021

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

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.13

.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.44

T;T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.0080

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

.;N;.

MutationTaster

Benign

0.99

PrimateAI

Benign

0.46

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

GERP RS

2.3

Varity_R

0.18

gMVP

0.62

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over