7-99856863-G-T

Variant names:

• chr7-99856863-G-T
• rs139450738
• NM_057095.3:c.829G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_057095.3(CYP3A43):​c.829G>T​(p.Asp277Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D277N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP3A43 NM_057095.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.829G>T	p.Asp277Tyr	missense	Exon 9 of 13	NP_476436.1	Q9HB55-1
	CYP3A43	NM_022820.5		c.829G>T	p.Asp277Tyr	missense	Exon 9 of 13	NP_073731.1	Q9HB55-2
	CYP3A43	NM_057096.4		c.829G>T	p.Asp277Tyr	missense	Exon 9 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.829G>T	p.Asp277Tyr	missense	Exon 9 of 13	ENSP00000346887.3	Q9HB55-1
	CYP3A43	ENST00000222382.5	TSL:1	c.829G>T	p.Asp277Tyr	missense	Exon 9 of 13	ENSP00000222382.5	Q9HB55-2
	CYP3A43	ENST00000312017.9	TSL:1	c.829G>T	p.Asp277Tyr	missense	Exon 9 of 12	ENSP00000312110.5	Q9HB55-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461446 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727018

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000287 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	0.16
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.24
MutPred		0.53		Loss of disorder (P = 0.0079)
MVP		0.87
MPC		0.20
ClinPred		1.0	D
GERP RS		-0.79
Varity_R		0.74
gMVP		0.61
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139450738; hg19: chr7-99454486;