rs35599367

Positions:

• chr7-99768693-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP5 BP4 BS1_Supporting BS2

The NM_017460.6(CYP3A4):​c.522-191C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0317 in 152,126 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars).

• Frequency: Genomes: 𝑓 0.032 (95 hom., cov: 32)
• Consequence: CYP3A4 NM_017460.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.53

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 Likely_benign. Variant got -5 ACMG points.

• PP5: Variant 7-99768693-G-A is Pathogenic according to our data. Variant chr7-99768693-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0317 (4825/152126) while in subpopulation NFE AF= 0.0492 (3348/67990). AF 95% confidence interval is 0.0479. There are 95 homozygotes in gnomad4. There are 2325 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 4825 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.522-191C>T		intron_variant		ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.522-191C>T		intron_variant			NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.522-191C>T		intron_variant			NM_017460.6	ENSP00000498939	P1
CYP3A4	ENST00000336411.7	c.522-191C>T		intron_variant		1		ENSP00000337915
CYP3A4	ENST00000354593.6	c.72-191C>T		intron_variant		5		ENSP00000346607
CYP3A4	ENST00000652018.1	c.375-191C>T		intron_variant				ENSP00000498733

Frequencies

GnomAD3 genomes AF: 0.0317 AC: 4824 AN: 152008 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00880

Gnomad AMI AF: 0.0538

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.0355

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0230

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0317 AC: 4825 AN: 152126 Hom.: 95 Cov.: 32 AF XY: 0.0313 AC XY: 2325 AN XY: 74376

Gnomad4 AFR AF: 0.00877

Gnomad4 AMR AF: 0.0255

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00915

Gnomad4 FIN AF: 0.0355

Gnomad4 NFE AF: 0.0492

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.0420 Hom.: 31

Bravo AF: 0.0306

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.34
DANN	Benign	0.60

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: rs35599367; hg19: chr7-99366316;