rs12721627

Variant names:

• chr7-99768470-G-A
• rs12721627
• NM_017460.6:c.554C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-99768470-G-A
• chr7-99768470-G-C

Variant summary

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

The NM_017460.6(CYP3A4):​c.554C>T​(p.Thr185Ile) variant causes a missense 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.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.31
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.554C>T	p.Thr185Ile	missense_variant	Exon 7 of 13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.554C>T	p.Thr185Ile	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.554C>T	p.Thr185Ile	missense_variant	Exon 7 of 13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000336411.7	c.554C>T	p.Thr185Ile	missense_variant	Exon 7 of 14	1		ENSP00000337915.3
CYP3A4	ENST00000652018.1	c.407C>T	p.Thr136Ile	missense_variant	Exon 5 of 11			ENSP00000498733.1
CYP3A4	ENST00000354593.6	c.104C>T	p.Thr35Ile	missense_variant	Exon 2 of 8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.82	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		5.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.055	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.87	P;P
Vest4		0.77
MutPred		0.66		.;Gain of helix (P = 0.2059);
MVP		0.83
MPC		0.47
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.58
Mutation Taster		=43/57	disease causing

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: rs12721627; hg19: chr7-99366093;