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_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. 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 NM_000765.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.49

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:):

ACMG classification

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	UniProt
CYP3A7	NM_000765.5	c.1057T>A	p.Leu353Met	missense_variant	11/13	ENST00000336374.4
CYP3A7-CYP3A51P	NM_001256497.3	c.1057T>A	p.Leu353Met	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A7	ENST00000336374.4	c.1057T>A	p.Leu353Met	missense_variant	11/13	1	NM_000765.5	P1
CYP3A7	ENST00000477357.5	n.1396T>A		non_coding_transcript_exon_variant	8/10	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

GnomAD3 exomes AF: 0.000650 AC: 163 AN: 250814 Hom.: 0 AF XY: 0.000649 AC XY: 88 AN XY: 135568

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.: 1 Cov.: 32 AF XY: 0.000838 AC XY: 609 AN XY: 727078

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.: 1 Cov.: 32 AF XY: 0.000926 AC XY: 69 AN XY: 74498

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.: 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

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	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;.
MutationTaster	Benign	0.99	N
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

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

Other links and lift over

dbSNP: rs141574193; hg19: chr7-99306854;