7-99859982-C-G

Position:

• chr7-99859982-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_057095.3(CYP3A43):​c.1018C>G​(p.Pro340Ala) variant causes a missense change. The variant allele was found at a frequency of 0.066 in 1,601,740 control chromosomes in the GnomAD database, including 6,316 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (2261 hom., cov: 32)
  • Exomes 𝑓: 0.060 (4055 hom.)
• Consequence: CYP3A43 NM_057095.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.25

Genes affected

CYP3A43 (HGNC:17450): (cytochrome P450 family 3 subfamily A member 43) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The encoded protein has a low level of testosterone hydroxylase activity, and may play a role in aging mechanisms and cancer progression. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004045546).
• BP6: Variant 7-99859982-C-G is Benign according to our data. Variant chr7-99859982-C-G is described in ClinVar as [Benign]. Clinvar id is 1278238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A43	NM_057095.3	c.1018C>G	p.Pro340Ala	missense_variant	10/13	ENST00000354829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A43	ENST00000354829.7	c.1018C>G	p.Pro340Ala	missense_variant	10/13	1	NM_057095.3	A1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19075 AN: 151942 Hom.: 2250 Cov.: 32

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0752

Gnomad ASJ AF: 0.0536

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.0552

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0552

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0648 AC: 15395 AN: 237488 Hom.: 1164 AF XY: 0.0609 AC XY: 7783 AN XY: 127888

Gnomad AFR exome AF: 0.320

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0599

Gnomad EAS exome AF: 0.000495

Gnomad SAS exome AF: 0.0408

Gnomad FIN exome AF: 0.0542

Gnomad NFE exome AF: 0.0537

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0597 AC: 86596 AN: 1449680 Hom.: 4055 Cov.: 31 AF XY: 0.0588 AC XY: 42361 AN XY: 720382

Gnomad4 AFR exome AF: 0.321

Gnomad4 AMR exome AF: 0.0439

Gnomad4 ASJ exome AF: 0.0577

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0433

Gnomad4 FIN exome AF: 0.0522

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0667

GnomAD4 genome AF: 0.126 AC: 19124 AN: 152060 Hom.: 2261 Cov.: 32 AF XY: 0.123 AC XY: 9149 AN XY: 74356

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.0750

Gnomad4 ASJ AF: 0.0536

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.0552

Gnomad4 NFE AF: 0.0552

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0649 Hom.: 345

Bravo AF: 0.134

TwinsUK AF: 0.0631 AC: 234

ALSPAC AF: 0.0597 AC: 230

ESP6500AA AF: 0.304 AC: 1338

ESP6500EA AF: 0.0488 AC: 420

ExAC AF: 0.0668 AC: 8108

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	This variant is associated with the following publications: (PMID: 25150845) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.12	T;.;.;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
MetaRNN	Benign	0.0040	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;.;.;M;M
MutationTaster	Benign	6.2e-11	P;P;P;P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D
REVEL	Benign	0.15
Sift	Uncertain	0.021	D;D;T;D;D;D
Sift4G	Benign	0.17	T;T;T;T;D;T
Polyphen		0.015	B;.;.;.;P;.
Vest4		0.16
MPC		0.025
ClinPred		0.083	T
GERP RS		1.6
Varity_R		0.66
gMVP		0.52

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: rs680055; hg19: chr7-99457605;