7-99758183-GT-GTT

Variant names:

• chr7-99758183-G-GT
• rs67666821
• NM_017460.6:c.1461dupA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The ENST00000651514.1(CYP3A4):​c.1461dupA​(p.Pro488ThrfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000445 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: CYP3A4 ENST00000651514.1 frameshift
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.411
• Publications: 41 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 7-99758183-G-GT is Benign according to our data. Variant chr7-99758183-G-GT is described in ClinVar as Likely_benign. ClinVar VariationId is 1318112.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 54 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651514.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	NM_017460.6	MANE Select	c.1461dupA	p.Pro488ThrfsTer7	frameshift	Exon 13 of 13	NP_059488.2
	CYP3A4	NM_001202855.3		c.1458dupA	p.Pro487ThrfsTer7	frameshift	Exon 13 of 13	NP_001189784.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A4	ENST00000651514.1	MANE Select	c.1461dupA	p.Pro488ThrfsTer7	frameshift	Exon 13 of 13	ENSP00000498939.1
	CYP3A4	ENST00000336411.7	TSL:1	c.1554dupA	p.Pro519ThrfsTer7	frameshift	Exon 14 of 14	ENSP00000337915.3
	CYP3A4	ENST00000652018.1		c.1314dupA	p.Pro439ThrfsTer7	frameshift	Exon 11 of 11	ENSP00000498733.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000342 AC: 86 AN: 251248 AF XY: 0.000302

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000326

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000455 AC: 665 AN: 1461718 Hom.: 0 Cov.: 30 AF XY: 0.000441 AC XY: 321 AN XY: 727158

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.00121 AC: 54 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000514 AC: 571 AN: 1111898

Other (OTH) AF: 0.000580 AC: 35 AN: 60382

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74476

African (AFR) AF: 0.0000481 AC: 2 AN: 41550

American (AMR) AF: 0.00151 AC: 23 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.0000581 Hom.: 0

Bravo AF: 0.000529

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=46/154	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs67666821; hg19: chr7-99355806;