chr7-99768360-A-G

Position:

• chr7-99768360-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017460.6(CYP3A4):​c.664T>C​(p.Ser222Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000431 in 1,613,720 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00060 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (6 hom.)
• Consequence: CYP3A4 NM_017460.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007305056).
• BP6: Variant 7-99768360-A-G is Benign according to our data. Variant chr7-99768360-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 91 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.664T>C	p.Ser222Pro	missense_variant	7/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.664T>C	p.Ser222Pro	missense_variant	7/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.664T>C	p.Ser222Pro	missense_variant	7/13		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000336411.7	c.664T>C	p.Ser222Pro	missense_variant	7/14	1		ENSP00000337915.3
CYP3A4	ENST00000652018.1	c.517T>C	p.Ser173Pro	missense_variant	5/11			ENSP00000498733.1
CYP3A4	ENST00000354593.6	c.214T>C	p.Ser72Pro	missense_variant	2/8	5		ENSP00000346607.2

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00724

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000956 AC: 240 AN: 251054 Hom.: 5 AF XY: 0.000855 AC XY: 116 AN XY: 135682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00999

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000414 AC: 605 AN: 1461404 Hom.: 6 Cov.: 32 AF XY: 0.000424 AC XY: 308 AN XY: 727028

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0100

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000597 AC: 91 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00724

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.000865 AC: 105

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.080	N
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0073	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Benign	0.14
Sift	Benign	0.099	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.74	P;B
Vest4		0.38
MVP		0.72
MPC		0.11
ClinPred		0.16	T
GERP RS		3.1
Varity_R		0.85

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: rs55785340; hg19: chr7-99365983;