5-96979486-C-T

Position:

• chr5-96979486-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005575.3(LNPEP):​c.368C>T​(p.Ser123Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LNPEP	NM_005575.3	c.368C>T	p.Ser123Phe	missense_variant	2/18	ENST00000231368.10	NP_005566.2
LNPEP	NM_175920.4	c.326C>T	p.Ser109Phe	missense_variant	2/18		NP_787116.2
LNPEP	XM_047417177.1	c.368C>T	p.Ser123Phe	missense_variant	2/16		XP_047273133.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LNPEP	ENST00000231368.10	c.368C>T	p.Ser123Phe	missense_variant	2/18	1	NM_005575.3	ENSP00000231368	P1
LNPEP	ENST00000395770.3	c.326C>T	p.Ser109Phe	missense_variant	2/18	1		ENSP00000379117

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.368C>T (p.S123F) alteration is located in exon 2 (coding exon 2) of the LNPEP gene. This alteration results from a C to T substitution at nucleotide position 368, causing the serine (S) at amino acid position 123 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	0.0072	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.96	D;.
Vest4		0.55
MutPred		0.46		Loss of catalytic residue at S123 (P = 0.1765);.;
MVP		0.17
MPC		0.72
ClinPred		0.87	D
GERP RS		6.1
Varity_R		0.091
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-96315190;