5-96979854-G-A

Position:

• chr5-96979854-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005575.3(LNPEP):​c.736G>A​(p.Val246Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09206554).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LNPEP	NM_005575.3	c.736G>A	p.Val246Ile	missense_variant	2/18	ENST00000231368.10
LNPEP	NM_175920.4	c.694G>A	p.Val232Ile	missense_variant	2/18
LNPEP	XM_047417177.1	c.736G>A	p.Val246Ile	missense_variant	2/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LNPEP	ENST00000231368.10	c.736G>A	p.Val246Ile	missense_variant	2/18	1	NM_005575.3	P1
LNPEP	ENST00000395770.3	c.694G>A	p.Val232Ile	missense_variant	2/18	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461720 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Feb 10, 2022

The c.736G>A (p.V246I) alteration is located in exon 2 (coding exon 2) of the LNPEP gene. This alteration results from a G to A substitution at nucleotide position 736, causing the valine (V) at amino acid position 246 to be replaced by an isoleucine (I). 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	0.069
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	14
DANN	Benign	0.60
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.080
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.092	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.41	N;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.11
Sift	Benign	0.65	T;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0	B;.
Vest4		0.21
MutPred		0.51		Loss of catalytic residue at V246 (P = 0.0235);.;
MVP		0.15
MPC		0.15
ClinPred		0.069	T
GERP RS		5.7
Varity_R		0.087
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: rs1790083092; hg19: chr5-96315558;