rs2303138

Variant names:

• chr5-97015006-G-A
• rs2303138
• NM_005575.3:c.2287G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005575.3(LNPEP):​c.2287G>A​(p.Ala763Thr) variant causes a missense change. The variant allele was found at a frequency of 0.092 in 1,601,346 control chromosomes in the GnomAD database, including 10,556 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 0.099 (1235 hom., cov: 32)
  • Exomes 𝑓: 0.091 (9321 hom.)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.97
• Publications: 58 publications found

Genes affected

LNPEP (HGNC:6656): (leucyl and cystinyl aminopeptidase) This gene encodes a zinc-dependent aminopeptidase that cleaves vasopressin, oxytocin, lys-bradykinin, met-enkephalin, dynorphin A and other peptide hormones. The protein can be secreted in maternal serum, reside in intracellular vesicles with the insulin-responsive glucose transporter GLUT4, or form a type II integral membrane glycoprotein. The protein catalyzes the final step in the conversion of angiotensinogen to angiotensin IV (AT4) and is also a receptor for AT4. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055810213).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LNPEP	NM_005575.3	c.2287G>A	p.Ala763Thr	missense_variant	Exon 13 of 18	ENST00000231368.10	NP_005566.2
LNPEP	NM_175920.4	c.2245G>A	p.Ala749Thr	missense_variant	Exon 13 of 18		NP_787116.2
LNPEP	XM_047417177.1	c.2287G>A	p.Ala763Thr	missense_variant	Exon 13 of 16		XP_047273133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LNPEP	ENST00000231368.10	c.2287G>A	p.Ala763Thr	missense_variant	Exon 13 of 18	1	NM_005575.3	ENSP00000231368.5
LNPEP	ENST00000395770.3	c.2245G>A	p.Ala749Thr	missense_variant	Exon 13 of 18	1		ENSP00000379117.3

Frequencies

GnomAD3 genomes AF: 0.0986 AC: 14991 AN: 151964 Hom.: 1236 Cov.: 32

Gnomad AFR AF: 0.0720

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.166

Gnomad FIN AF: 0.0725

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0736

Gnomad OTH AF: 0.0995

GnomAD2 exomes AF: 0.132 AC: 32388 AN: 245798 AF XY: 0.127

Gnomad AFR exome AF: 0.0661

Gnomad AMR exome AF: 0.230

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.460

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0703

Gnomad OTH exome AF: 0.0982

GnomAD4 exome AF: 0.0914 AC: 132405 AN: 1449264 Hom.: 9321 Cov.: 29 AF XY: 0.0920 AC XY: 66337 AN XY: 720686

African (AFR) AF: 0.0701 AC: 2328 AN: 33204

American (AMR) AF: 0.221 AC: 9624 AN: 43456

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2727 AN: 25990

East Asian (EAS) AF: 0.402 AC: 15690 AN: 39004

South Asian (SAS) AF: 0.161 AC: 13436 AN: 83490

European-Finnish (FIN) AF: 0.0711 AC: 3792 AN: 53302

Middle Eastern (MID) AF: 0.0688 AC: 395 AN: 5744

European-Non Finnish (NFE) AF: 0.0710 AC: 78436 AN: 1105146

Other (OTH) AF: 0.0997 AC: 5977 AN: 59928

GnomAD4 genome AF: 0.0985 AC: 14986 AN: 152082 Hom.: 1235 Cov.: 32 AF XY: 0.102 AC XY: 7562 AN XY: 74360

African (AFR) AF: 0.0719 AC: 2983 AN: 41508

American (AMR) AF: 0.164 AC: 2501 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 382 AN: 3466

East Asian (EAS) AF: 0.426 AC: 2206 AN: 5174

South Asian (SAS) AF: 0.166 AC: 803 AN: 4828

European-Finnish (FIN) AF: 0.0725 AC: 768 AN: 10598

Middle Eastern (MID) AF: 0.0514 AC: 15 AN: 292

European-Non Finnish (NFE) AF: 0.0736 AC: 5002 AN: 67948

Other (OTH) AF: 0.0980 AC: 207 AN: 2112

Alfa AF: 0.0878 Hom.: 4238

Bravo AF: 0.108

TwinsUK AF: 0.0658 AC: 244

ALSPAC AF: 0.0737 AC: 284

ESP6500AA AF: 0.0710 AC: 313

ESP6500EA AF: 0.0742 AC: 638

ExAC AF: 0.129 AC: 15714

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0056	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		5.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.96	N;N
REVEL	Benign	0.098
Sift	Benign	0.25	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.62	P;.
Vest4		0.26
MPC		0.72
ClinPred		0.035	T
GERP RS		5.5
Varity_R		0.45
gMVP		0.36
Mutation Taster		=94/6	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: rs2303138; hg19: chr5-96350710; COSMIC: COSV107223146;