7-99672720-G-T

Variant names:

• chr7-99672720-G-T
• rs8175346
• NM_000777.5:c.219-41C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000777.5(CYP3A5):​c.219-41C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.017 in 1,611,512 control chromosomes in the GnomAD database, including 253 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 0.013 (21 hom., cov: 32)
  • Exomes 𝑓: 0.017 (232 hom.)
• Consequence: CYP3A5 NM_000777.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.136
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (2019/152186) while in subpopulation NFE AF = 0.0189 (1285/68000). AF 95% confidence interval is 0.018. There are 21 homozygotes in GnomAd4. There are 977 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2019 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.219-41C>A		intron_variant	Intron 3 of 12	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.219-41C>A		intron_variant	Intron 3 of 12	1	NM_000777.5	ENSP00000222982.4

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2024 AN: 152068 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00830

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0144 AC: 3567 AN: 247778 AF XY: 0.0149

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0190

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0174 AC: 25349 AN: 1459326 Hom.: 232 Cov.: 31 AF XY: 0.0172 AC XY: 12501 AN XY: 725812

African (AFR) AF: 0.00255 AC: 85 AN: 33362

American (AMR) AF: 0.0126 AC: 559 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 588 AN: 26048

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39662

South Asian (SAS) AF: 0.00936 AC: 801 AN: 85576

European-Finnish (FIN) AF: 0.0142 AC: 755 AN: 53328

Middle Eastern (MID) AF: 0.0155 AC: 89 AN: 5760

European-Non Finnish (NFE) AF: 0.0193 AC: 21432 AN: 1111036

Other (OTH) AF: 0.0172 AC: 1039 AN: 60280

GnomAD4 genome AF: 0.0133 AC: 2019 AN: 152186 Hom.: 21 Cov.: 32 AF XY: 0.0131 AC XY: 977 AN XY: 74420

African (AFR) AF: 0.00337 AC: 140 AN: 41514

American (AMR) AF: 0.0164 AC: 251 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00789 AC: 38 AN: 4814

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1285 AN: 68000

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0143 Hom.: 14

Bravo AF: 0.0134

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.83
DANN	Benign	0.57
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=99/1	polymorphism

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: rs8175346; hg19: chr7-99270343; COSMIC: COSV56119962;