7-99768445-G-C

Variant names:

• chr7-99768445-G-C
• rs4987159
• NM_017460.6:c.579C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017460.6(CYP3A4):​c.579C>G​(p.Ile193Met) 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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I193I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.42
• Publications: 12 publications found

Genes affected

CYP3A4 (HGNC:2637): (cytochrome P450 family 3 subfamily A member 4) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and its expression is induced by glucocorticoids and some pharmacological agents. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam, erythromycin, and chloroquine. The enzyme also metabolizes some steroids and carcinogens. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents a transcript variant of CYP3A4. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2020]

CYP3A4 Gene-Disease associations (from GenCC):

• vitamin D-dependent rickets, type 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21415374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.579C>G	p.Ile193Met	missense_variant	Exon 7 of 13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.579C>G	p.Ile193Met	missense_variant	Exon 7 of 13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.579C>G	p.Ile193Met	missense_variant	Exon 7 of 13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000336411.7	c.579C>G	p.Ile193Met	missense_variant	Exon 7 of 14	1		ENSP00000337915.3
CYP3A4	ENST00000652018.1	c.432C>G	p.Ile144Met	missense_variant	Exon 5 of 11			ENSP00000498733.1
CYP3A4	ENST00000354593.6	c.129C>G	p.Ile43Met	missense_variant	Exon 2 of 8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251324 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.9
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		-1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.025	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.26	B;B
Vest4		0.40
MutPred		0.65		.;Gain of disorder (P = 0.0428);
MVP		0.53
MPC		0.14
ClinPred		0.16	T
GERP RS		-1.4
Varity_R		0.56
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4987159; hg19: chr7-99366068;