rs35599367

Variant names:

• chr7-99768693-G-A
• rs35599367
• NM_017460.6:c.522-191C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-99768693-G-A
• chr7-99768693-G-C
• chr7-99768693-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 352 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4825 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A4	NM_017460.6	c.522-191C>T		intron_variant	Intron 6 of 12	ENST00000651514.1	NP_059488.2
CYP3A4	NM_001202855.3	c.522-191C>T		intron_variant	Intron 6 of 12		NP_001189784.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A4	ENST00000651514.1	c.522-191C>T		intron_variant	Intron 6 of 12		NM_017460.6	ENSP00000498939.1
CYP3A4	ENST00000336411.7	c.522-191C>T		intron_variant	Intron 6 of 13	1		ENSP00000337915.3
CYP3A4	ENST00000652018.1	c.375-191C>T		intron_variant	Intron 4 of 10			ENSP00000498733.1
CYP3A4	ENST00000354593.6	c.72-191C>T		intron_variant	Intron 1 of 7	5		ENSP00000346607.2

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

African (AFR) AF: 0.00877 AC: 364 AN: 41506

American (AMR) AF: 0.0255 AC: 389 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00915 AC: 44 AN: 4810

European-Finnish (FIN) AF: 0.0355 AC: 376 AN: 10578

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3348 AN: 67990

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0406 Hom.: 277

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
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs35599367; hg19: chr7-99366316;