chr7-99652613-G-T

Variant names:

• chr7-99652613-G-T
• rs28365083
• NM_000777.5:c.1193C>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 51 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 -8 ACMG points.

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

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.1193C>A	p.Thr398Asn	missense	Exon 11 of 13	NP_000768.1	P20815-1
	CYP3A5	NM_001291830.2		c.1163C>A	p.Thr388Asn	missense	Exon 12 of 14	NP_001278759.1
	CYP3A5	NM_001291829.2		c.854C>A	p.Thr285Asn	missense	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.1193C>A	p.Thr398Asn	missense	Exon 11 of 13	ENSP00000222982.4	P20815-1
	CYP3A5	ENST00000882638.1		c.1268C>A	p.Thr423Asn	missense	Exon 12 of 14	ENSP00000552697.1
	CYP3A5	ENST00000882636.1		c.1175C>A	p.Thr392Asn	missense	Exon 11 of 13	ENSP00000552695.1

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

GnomAD2 exomes AF: 0.00325 AC: 817 AN: 251382 AF XY: 0.00314

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 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

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00174 AC: 93 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00581 AC: 6463 AN: 1111930

Other (OTH) AF: 0.00250 AC: 151 AN: 60396

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

African (AFR) AF: 0.00125 AC: 52 AN: 41546

American (AMR) AF: 0.000981 AC: 15 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00543 AC: 369 AN: 68008

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00494 Hom.: 60

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 v4.9

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
PhyloP100		-1.0
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
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs28365083; hg19: chr7-99250236; COSMIC: COSV99033822;