7-99848168-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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 (★★).

• 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, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 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 VariationId is 735139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

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>T	p.Met145Ile	missense splice_region	Exon 6 of 13	NP_476436.1	Q9HB55-1
	CYP3A43	NM_022820.5		c.435G>T	p.Met145Ile	missense splice_region	Exon 6 of 13	NP_073731.1	Q9HB55-2
	CYP3A43	NM_057096.4		c.435G>T	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>T	p.Met145Ile	missense splice_region	Exon 6 of 13	ENSP00000346887.3	Q9HB55-1
	CYP3A43	ENST00000222382.5	TSL:1	c.435G>T	p.Met145Ile	missense splice_region	Exon 6 of 13	ENSP00000222382.5	Q9HB55-2
	CYP3A43	ENST00000312017.9	TSL:1	c.435G>T	p.Met145Ile	missense splice_region	Exon 6 of 12	ENSP00000312110.5	Q9HB55-3

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

GnomAD2 exomes AF: 0.00255 AC: 641 AN: 251256 AF XY: 0.00190

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 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

African (AFR) AF: 0.0361 AC: 1207 AN: 33478

American (AMR) AF: 0.00168 AC: 75 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111948

Other (OTH) AF: 0.00185 AC: 112 AN: 60388

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

African (AFR) AF: 0.0348 AC: 1447 AN: 41554

American (AMR) AF: 0.00150 AC: 23 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00338 Hom.: 42

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.32
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		0.11	T
GERP RS		2.9
Varity_R		0.57
gMVP		0.81
Mutation Taster		=57/43	polymorphism

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

Other links and lift over

dbSNP: rs45450092; hg19: chr7-99445791;