rs28365083

Positions:

• chr7-99652613-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000777.5(CYP3A5):​c.1193C>A​(p.Thr398Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,614,026 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0030 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (21 hom.)
• Consequence: CYP3A5 NM_000777.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04

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:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0249556).
• BS2: High AC in GnomAd4 at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP3A5	NM_000777.5	c.1193C>A	p.Thr398Asn	missense_variant	11/13	ENST00000222982.8	NP_000768.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP3A5	ENST00000222982.8	c.1193C>A	p.Thr398Asn	missense_variant	11/13	1	NM_000777.5	ENSP00000222982	P1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152116 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00543

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00325 AC: 817 AN: 251382 Hom.: 3 AF XY: 0.00314 AC XY: 426 AN XY: 135876

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00465 AC: 6798 AN: 1461792 Hom.: 21 Cov.: 31 AF XY: 0.00456 AC XY: 3313 AN XY: 727214

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00581

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74434

Gnomad4 AFR AF: 0.00125

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00543

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00501 Hom.: 54

Bravo AF: 0.00300

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00352 AC: 428

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00492

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.013
DANN	Benign	0.80
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.11
Sift	Benign	0.046	D
Sift4G	Uncertain	0.040	D
Polyphen		0.0030	B
Vest4		0.21
MVP		0.45
MPC		0.26
ClinPred		0.013	T
GERP RS		-2.7
Varity_R		0.18
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28365083; hg19: chr7-99250236; COSMIC: COSV99033822;