7-99849685-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_057095.3(CYP3A43):c.661C>G(p.Leu221Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP3A43 NM_057095.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1900537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A43	NM_057095.3	c.661C>G	p.Leu221Val	missense_variant	7/13	ENST00000354829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A43	ENST00000354829.7	c.661C>G	p.Leu221Val	missense_variant	7/13	1	NM_057095.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.661C>G (p.L221V) alteration is located in exon 7 (coding exon 7) of the CYP3A43 gene. This alteration results from a C to G substitution at nucleotide position 661, causing the leucine (L) at amino acid position 221 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.97	N;N;N
REVEL	Benign	0.099
Sift	Benign	0.063	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0060	B;B;.
Vest4		0.057
MutPred		0.63		Loss of stability (P = 0.3678);Loss of stability (P = 0.3678);Loss of stability (P = 0.3678);
MVP		0.32
MPC		0.027
ClinPred		0.055	T
GERP RS		-5.3
Varity_R		0.11
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-99447308;