rs56324128

Positions:

• chr7-99778079-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_017460.6(CYP3A4):​c.167G>A​(p.Gly56Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000579 in 1,610,894 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (1 hom.)
• Consequence: CYP3A4 NM_017460.6 missense, splice_region
• Scores: Splicing: ADA: 0.8556
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09765619).
• BP6: Variant 7-99778079-C-T is Benign according to our data. Variant chr7-99778079-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.167G>A	p.Gly56Asp	missense_variant, splice_region_variant	3/13	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.167G>A	p.Gly56Asp	missense_variant, splice_region_variant	3/13		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.167G>A	p.Gly56Asp	missense_variant, splice_region_variant	3/13		NM_017460.6	ENSP00000498939.1

Frequencies

GnomAD3 genomes AF: 0.000868 AC: 132 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000559 AC: 140 AN: 250314 Hom.: 0 AF XY: 0.000458 AC XY: 62 AN XY: 135278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.000874

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000548 AC: 800 AN: 1458624 Hom.: 1 Cov.: 29 AF XY: 0.000577 AC XY: 419 AN XY: 725856

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.000619

Gnomad4 OTH exome AF: 0.000448

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74456

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00163

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000997 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000568 AC: 69

EpiCase AF: 0.000873

EpiControl AF: 0.000652

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.098	T;T
MetaSVM	Uncertain	0.061	D
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.76
MVP		0.87
MPC		0.52
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.86
dbscSNV1_RF	Pathogenic	0.86
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: rs56324128; hg19: chr7-99375702;