Genetic Variant NM_057095.3:c.1018C>A (chr7-99859982-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_057095.3(CYP3A43):c.1018C>A(p.Pro340Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P340A) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CYP3A43
NM_057095.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.25

Publications

43 publications found

Variant links:

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]

CYP3A43 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A43	NM_057095.3 link	c.1018C>A	p.Pro340Thr	missense_variant	Exon 10 of 13	ENST00000354829.7	NP_476436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A43	ENST00000354829.7 link	c.1018C>A	p.Pro340Thr	missense_variant	Exon 10 of 13	1	NM_057095.3	ENSP00000346887.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449770

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720422

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33212

American (AMR)

AF:

0.00

AC:

AN:

43428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25170

East Asian (EAS)

AF:

0.00

AC:

AN:

39566

South Asian (SAS)

AF:

0.00

AC:

AN:

83596

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52828

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106364

Other (OTH)

AF:

0.00

AC:

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;.;.;.;.

Eigen

Benign

0.033

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.046

MetaRNN

Pathogenic

0.80

D;D;D;D;D;D

MetaSVM

Uncertain

0.25

MutationAssessor

Uncertain

2.8

M;.;.;.;M;M

PhyloP100

4.3

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-7.2

D;D;D;D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Benign

0.096

T;T;T;T;D;T

Polyphen

0.23

B;.;.;.;D;.

Vest4

0.36

MutPred

0.47

Loss of methylation at K342 (P = 0.1034);.;.;.;Loss of methylation at K342 (P = 0.1034);Loss of methylation at K342 (P = 0.1034);

MVP

0.89

MPC

0.032

ClinPred

0.97

GERP RS

1.6

Varity_R

0.87

gMVP

0.60

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over