9-135564268-T-A

Variant names:

• chr9-135564268-T-A
• rs1832472562
• NM_002571.4:c.335T>A

Variant summary

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

The NM_002571.4(PAEP):​c.335T>A​(p.Leu112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L112V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PAEP NM_002571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.435
• Publications: 0 publications found

Genes affected

PAEP (HGNC:8573): (progestagen associated endometrial protein) This gene is a member of the kernel lipocalin superfamily whose members share relatively low sequence similarity but have highly conserved exon/intron structure and three-dimensional protein folding. Most lipocalins are clustered on the long arm of chromosome 9. The encoded glycoprotein has been previously referred to as pregnancy-associated endometrial alpha-2-globulin, placental protein 14, and glycodelin, but has been officially named progestagen-associated endometrial protein. Three distinct forms, with identical protein backbones but different glycosylation profiles, are found in amniotic fluid, follicular fluid and seminal plasma of the reproductive system. These glycoproteins have distinct and essential roles in regulating a uterine environment suitable for pregnancy and in the timing and occurrence of the appropriate sequence of events in the fertilization process. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

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
PAEP	NM_002571.4	c.335T>A	p.Leu112Gln	missense_variant	Exon 4 of 7	ENST00000479141.6	NP_002562.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAEP	ENST00000479141.6	c.335T>A	p.Leu112Gln	missense_variant	Exon 4 of 7	1	NM_002571.4	ENSP00000417898.1
PAEP	ENST00000371766.6	c.335T>A	p.Leu112Gln	missense_variant	Exon 4 of 7	1		ENSP00000360831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.335T>A (p.L112Q) alteration is located in exon 4 (coding exon 4) of the PAEP gene. This alteration results from a T to A substitution at nucleotide position 335, causing the leucine (L) at amino acid position 112 to be replaced by a glutamine (Q). 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.52	.;.;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;L;.
PhyloP100		0.43
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.059	T;T;T;T
Polyphen		1.0	D;D;D;.
Vest4		0.61
MutPred		0.76		Loss of stability (P = 0.0736);Loss of stability (P = 0.0736);Loss of stability (P = 0.0736);.;
MVP		0.23
MPC		0.95
ClinPred		0.63	D
GERP RS		0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.71
Mutation Taster		=89/11	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: rs1832472562; hg19: chr9-138456114;