rs12520455

Variant names:

• chr5-97003542-A-T
• rs12520455
• NM_005575.3:c.1781A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005575.3(LNPEP):​c.1781A>T​(p.Asn594Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 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: not found (cov: 31)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.13
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LNPEP	NM_005575.3	c.1781A>T	p.Asn594Ile	missense_variant	Exon 9 of 18	ENST00000231368.10	NP_005566.2
LNPEP	NM_175920.4	c.1739A>T	p.Asn580Ile	missense_variant	Exon 9 of 18		NP_787116.2
LNPEP	XM_047417177.1	c.1781A>T	p.Asn594Ile	missense_variant	Exon 9 of 16		XP_047273133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LNPEP	ENST00000231368.10	c.1781A>T	p.Asn594Ile	missense_variant	Exon 9 of 18	1	NM_005575.3	ENSP00000231368.5
LNPEP	ENST00000395770.3	c.1739A>T	p.Asn580Ile	missense_variant	Exon 9 of 18	1		ENSP00000379117.3
LNPEP	ENST00000473914.1	n.386A>T		non_coding_transcript_exon_variant	Exon 3 of 4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Uncertain	0.61	D;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0079	T
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.
PhyloP100		3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.074
Sift	Benign	0.073	T;T
Sift4G	Benign	0.066	T;T
Polyphen		0.015	B;.
Vest4		0.87
MutPred		0.20		Loss of disorder (P = 0.1268);.;
MVP		0.17
MPC		0.67
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.35
gMVP		0.56
Mutation Taster		=58/42	polymorphism

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: rs12520455; hg19: chr5-96339246;