NM_005575.3:c.2887A>G

Variant names:

• chr5-97027755-A-G
• rs11746232
• NM_005575.3:c.2887A>G

Variant summary

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

The NM_005575.3(LNPEP):​c.2887A>G​(p.Ile963Val) variant causes a missense change. The variant allele was found at a frequency of 0.0927 in 1,604,980 control chromosomes in the GnomAD database, including 7,823 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.078 (569 hom., cov: 32)
  • Exomes 𝑓: 0.094 (7254 hom.)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.58
• Publications: 24 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=0.0019505918).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005575.3. 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
	LNPEP	NM_005575.3	MANE Select	c.2887A>G	p.Ile963Val	missense	Exon 17 of 18	NP_005566.2	Q9UIQ6-1
	LNPEP	NM_175920.4		c.2845A>G	p.Ile949Val	missense	Exon 17 of 18	NP_787116.2	Q9UIQ6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LNPEP	ENST00000231368.10	TSL:1 MANE Select	c.2887A>G	p.Ile963Val	missense	Exon 17 of 18	ENSP00000231368.5	Q9UIQ6-1
	LNPEP	ENST00000395770.3	TSL:1	c.2845A>G	p.Ile949Val	missense	Exon 17 of 18	ENSP00000379117.3	Q9UIQ6-2
	LNPEP	ENST00000930837.1		c.2884A>G	p.Ile962Val	missense	Exon 17 of 18	ENSP00000600896.1

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11853 AN: 152160 Hom.: 570 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0791

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0914 AC: 22947 AN: 251122 AF XY: 0.0980

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.0563

Gnomad ASJ exome AF: 0.140

Gnomad EAS exome AF: 0.00141

Gnomad FIN exome AF: 0.0982

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0942 AC: 136892 AN: 1452702 Hom.: 7254 Cov.: 29 AF XY: 0.0972 AC XY: 70288 AN XY: 723268

African (AFR) AF: 0.0299 AC: 998 AN: 33342

American (AMR) AF: 0.0595 AC: 2659 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3641 AN: 26090

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39666

South Asian (SAS) AF: 0.147 AC: 12613 AN: 86000

European-Finnish (FIN) AF: 0.102 AC: 5466 AN: 53384

Middle Eastern (MID) AF: 0.162 AC: 931 AN: 5748

European-Non Finnish (NFE) AF: 0.0949 AC: 104715 AN: 1103710

Other (OTH) AF: 0.0972 AC: 5839 AN: 60058

GnomAD4 genome AF: 0.0778 AC: 11850 AN: 152278 Hom.: 569 Cov.: 32 AF XY: 0.0784 AC XY: 5836 AN XY: 74448

African (AFR) AF: 0.0329 AC: 1367 AN: 41552

American (AMR) AF: 0.0789 AC: 1207 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 502 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.151 AC: 728 AN: 4828

European-Finnish (FIN) AF: 0.0959 AC: 1017 AN: 10604

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0991 AC: 6743 AN: 68024

Other (OTH) AF: 0.0992 AC: 210 AN: 2116

Alfa AF: 0.0938 Hom.: 2639

Bravo AF: 0.0724

TwinsUK AF: 0.0971 AC: 360

ALSPAC AF: 0.0916 AC: 353

ESP6500AA AF: 0.0322 AC: 142

ESP6500EA AF: 0.0960 AC: 826

ExAC AF: 0.0938 AC: 11386

Asia WGS AF: 0.0590 AC: 207 AN: 3476

EpiCase AF: 0.112

EpiControl AF: 0.111

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.6
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.095
Sift	Benign	0.051	T
Sift4G	Benign	0.16	T
Polyphen		0.0060	B
Vest4		0.032
MPC		0.18
ClinPred		0.016	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.26
Mutation Taster		=95/5	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: rs11746232; hg19: chr5-96363459; COSMIC: COSV51477058;