7-99848168-G-T

Position:

• chr7-99848168-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_057095.3(CYP3A43):​c.435G>T​(p.Met145Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00181 in 1,614,070 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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 0.0098 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (20 hom.)
• Consequence: CYP3A43 NM_057095.3 missense, splice_region
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.80

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061385036).
• BP6: Variant 7-99848168-G-T is Benign according to our data. Variant chr7-99848168-G-T is described in ClinVar as [Benign]. Clinvar id is 735139.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00984 (1498/152288) while in subpopulation AFR AF= 0.0348 (1447/41554). AF 95% confidence interval is 0.0333. There are 27 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP3A43	NM_057095.3	c.435G>T	p.Met145Ile	missense_variant, splice_region_variant	6/13	ENST00000354829.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP3A43	ENST00000354829.7	c.435G>T	p.Met145Ile	missense_variant, splice_region_variant	6/13	1	NM_057095.3	A1

Frequencies

GnomAD3 genomes AF: 0.00984 AC: 1497 AN: 152170 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00255 AC: 641 AN: 251256 Hom.: 8 AF XY: 0.00190 AC XY: 258 AN XY: 135798

Gnomad AFR exome AF: 0.0356

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000972 AC: 1421 AN: 1461782 Hom.: 20 Cov.: 30 AF XY: 0.000825 AC XY: 600 AN XY: 727190

Gnomad4 AFR exome AF: 0.0361

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00984 AC: 1498 AN: 152288 Hom.: 27 Cov.: 32 AF XY: 0.00948 AC XY: 706 AN XY: 74474

Gnomad4 AFR AF: 0.0348

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00192 Hom.: 12

Bravo AF: 0.0114

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	23
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;D;D
MetaRNN	Benign	0.0061	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.3	M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.045	D;D;D
Sift4G	Benign	0.084	T;D;T
Polyphen		0.88	P;P;.
Vest4		0.65
MutPred		0.65		Gain of catalytic residue at P147 (P = 0.0391);Gain of catalytic residue at P147 (P = 0.0391);Gain of catalytic residue at P147 (P = 0.0391);
MVP		0.66
MPC		0.20
ClinPred		0.11	T
GERP RS		2.9
Varity_R		0.57
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45450092; hg19: chr7-99445791;