5-96979413-C-T

Variant names:

• chr5-96979413-C-T
• NM_005575.3:c.295C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005575.3(LNPEP):​c.295C>T​(p.Pro99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 0.0000014 (0 hom.)
• Consequence: LNPEP NM_005575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.180
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029788584).

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.295C>T	p.Pro99Ser	missense	Exon 2 of 18	NP_005566.2	Q9UIQ6-1
	LNPEP	NM_175920.4		c.253C>T	p.Pro85Ser	missense	Exon 2 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.295C>T	p.Pro99Ser	missense	Exon 2 of 18	ENSP00000231368.5	Q9UIQ6-1
	LNPEP	ENST00000395770.3	TSL:1	c.253C>T	p.Pro85Ser	missense	Exon 2 of 18	ENSP00000379117.3	Q9UIQ6-2
	LNPEP	ENST00000930837.1		c.295C>T	p.Pro99Ser	missense	Exon 2 of 18	ENSP00000600896.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461784 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.2
DANN	Benign	0.67
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.11	N
PhyloP100		-0.18
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.045
Sift	Benign	0.53	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.21		Gain of phosphorylation at P99 (P = 0.0203)
MVP		0.12
MPC		0.19
ClinPred		0.024	T
GERP RS		-0.35
Varity_R		0.092
gMVP		0.35
Mutation Taster		=76/24	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

hg19: chr5-96315117;