rs11746232

chr5-97027755-A-Gchr5-97027755-A-T

Variant summary

Our verdict is Benign. Variant got -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. 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 0.078 (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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LNPEP	NM_005575.3	c.2887A>G	p.Ile963Val	missense_variant	17/18	ENST00000231368.10
LNPEP	NM_175920.4	c.2845A>G	p.Ile949Val	missense_variant	17/18
LNPEP	XM_047417177.1	c.2584A>G	p.Ile862Val	missense_variant	15/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LNPEP	ENST00000231368.10	c.2887A>G	p.Ile963Val	missense_variant	17/18	1	NM_005575.3	P1
LNPEP	ENST00000395770.3	c.2845A>G	p.Ile949Val	missense_variant	17/18	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

GnomAD3 exomes AF: 0.0914 AC: 22947 AN: 251122 Hom.: 1338 AF XY: 0.0980 AC XY: 13295 AN XY: 135718

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 SAS exome AF: 0.143

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

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.0595

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0949

Gnomad4 OTH exome AF: 0.0972

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

Gnomad4 AFR AF: 0.0329

Gnomad4 AMR AF: 0.0789

Gnomad4 ASJ AF: 0.145

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.0959

Gnomad4 NFE AF: 0.0991

Gnomad4 OTH AF: 0.0992

Alfa AF: 0.0973 Hom.: 2081

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 v4.3

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;T
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	0.000024	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.73	N;N
REVEL	Benign	0.095
Sift	Benign	0.051	T;T
Sift4G	Benign	0.16	T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs11746232; hg19: chr5-96363459; COSMIC: COSV51477058;