chr7-99848168-G-A

Variant names:

• chr7-99848168-G-A
• rs45450092
• NM_057095.3:c.435G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_057095.3(CYP3A43):​c.435G>A​(p.Met145Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP3A43 NM_057095.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.80
• Publications: 11 publications found

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

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, 0.837

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_057095.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A43	NM_057095.3	MANE Select	c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 13	NP_476436.1	Q9HB55-1
	CYP3A43	NM_022820.5		c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 13	NP_073731.1	Q9HB55-2
	CYP3A43	NM_057096.4		c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 12	NP_476437.1	Q9HB55-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A43	ENST00000354829.7	TSL:1 MANE Select	c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 13	ENSP00000346887.3	Q9HB55-1
	CYP3A43	ENST00000222382.5	TSL:1	c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 13	ENSP00000222382.5	Q9HB55-2
	CYP3A43	ENST00000312017.9	TSL:1	c.435G>A	p.Met145Ile	missense splice_region	Exon 6 of 12	ENSP00000312110.5	Q9HB55-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 42

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.34
Sift	Benign	0.045	D
Sift4G	Benign	0.084	T
Polyphen		0.88	P
Vest4		0.65
MutPred		0.65		Gain of catalytic residue at P147 (P = 0.0391)
MVP		0.66
MPC		0.20
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.57
gMVP		0.81
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.22		Position offset: -2

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

Other links and lift over

dbSNP: rs45450092; hg19: chr7-99445791;