rs41303343

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.1035dupT	p.Thr346TyrfsTer3	frameshift_variant	Exon 11 of 13	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.1035dupT	p.Thr346TyrfsTer3	frameshift_variant	Exon 11 of 13	1	NM_000777.5	ENSP00000222982.4

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

GnomAD3 exomes AF: 0.00731 AC: 1832 AN: 250480 Hom.: 82 AF XY: 0.00541 AC XY: 732 AN XY: 135354

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 SAS exome AF: 0.0000985

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

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00549

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00592

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

Gnomad4 AFR AF: 0.101

Gnomad4 AMR AF: 0.00929

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0213

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

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CYP3A5-related disorder Benign:1

Jul 21, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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: rs41303343; hg19: chr7-99250393;