7-99763979-A-G

Position:

• chr7-99763979-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_017460.6(CYP3A4):​c.902T>C​(p.Ile301Thr) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-99763979-A-G is Pathogenic according to our data. Variant chr7-99763979-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 982369.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21317032). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.902T>C	p.Ile301Thr	missense_variant	10/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.899T>C	p.Ile300Thr	missense_variant	10/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.902T>C	p.Ile301Thr	missense_variant	10/13		NM_017460.6	ENSP00000498939	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin D-dependent rickets, type 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 26, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.1	.;M
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.25
Sift	Benign	0.075	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.096	B;B
Vest4		0.23
MutPred		0.59		.;Loss of stability (P = 0.008);
MVP		0.57
MPC		0.34
ClinPred		0.94	D
GERP RS		2.2
Varity_R		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1815413655; hg19: chr7-99361602; COSMIC: COSV100315375; COSMIC: COSV100315375;