rs41303343

Variant names:

• chr7-99652770-T-TA
• rs41303343
• NM_000777.5:c.1035dupT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000777.5(CYP3A5):​c.1035dupT​(p.Thr346TyrfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00527 in 1,613,102 control chromosomes in the GnomAD database, including 441 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.029 (243 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (198 hom.)
• Consequence: CYP3A5 NM_000777.5 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.542
• Publications: 142 publications found

Genes affected

CYP3A5 (HGNC:2638): (cytochrome P450 family 3 subfamily A member 5) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. The encoded protein metabolizes drugs as well as the steroid hormones testosterone and progesterone. This gene is part of a cluster of cytochrome P450 genes on chromosome 7q21.1. Two pseudogenes of this gene have been identified within this cluster on chromosome 7. Expression of this gene is widely variable among populations, and a single nucleotide polymorphism that affects transcript splicing has been associated with susceptibility to hypertensions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

ZSCAN25 (HGNC:21961): (zinc finger and SCAN domain containing 25) This gene encodes a protein that bears some similarity to zinc finger proteins, which are involved in DNA binding and protein-protein interactions. Multiple alternatively spliced transcript variants have been identified, but the full-length nature for most of them has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 7-99652770-T-TA is Benign according to our data. Variant chr7-99652770-T-TA is described in ClinVar as Likely_benign. ClinVar VariationId is 3038280.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0985 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000777.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	NM_000777.5	MANE Select	c.1035dupT	p.Thr346TyrfsTer3	frameshift	Exon 11 of 13	NP_000768.1	P20815-1
	CYP3A5	NM_001291830.2		c.1005dupT	p.Thr336TyrfsTer3	frameshift	Exon 12 of 14	NP_001278759.1
	CYP3A5	NM_001291829.2		c.696dupT	p.Thr233TyrfsTer3	frameshift	Exon 12 of 14	NP_001278758.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP3A5	ENST00000222982.8	TSL:1 MANE Select	c.1035dupT	p.Thr346TyrfsTer3	frameshift	Exon 11 of 13	ENSP00000222982.4	P20815-1
	CYP3A5	ENST00000882638.1		c.1110dupT	p.Thr371TyrfsTer3	frameshift	Exon 12 of 14	ENSP00000552697.1
	CYP3A5	ENST00000882636.1		c.1017dupT	p.Thr340TyrfsTer3	frameshift	Exon 11 of 13	ENSP00000552695.1

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4407 AN: 152148 Hom.: 244 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00936

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00731 AC: 1832 AN: 250480 AF XY: 0.00541

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00450

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00280 AC: 4085 AN: 1460836 Hom.: 198 Cov.: 30 AF XY: 0.00240 AC XY: 1742 AN XY: 726704

African (AFR) AF: 0.102 AC: 3408 AN: 33450

American (AMR) AF: 0.00549 AC: 245 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111348

Other (OTH) AF: 0.00592 AC: 357 AN: 60342

GnomAD4 genome AF: 0.0290 AC: 4411 AN: 152266 Hom.: 243 Cov.: 31 AF XY: 0.0271 AC XY: 2017 AN XY: 74456

African (AFR) AF: 0.101 AC: 4197 AN: 41528

American (AMR) AF: 0.00929 AC: 142 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.00474 Hom.: 23

Bravo AF: 0.0327

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYP3A5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.54
Mutation Taster		=164/36	polymorphism (auto)

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: rs41303343; hg19: chr7-99250393; COSMIC: COSV56122495;