9-135564321-A-C

Variant names:

• chr9-135564321-A-C
• rs1350535956
• NM_002571.4:c.388A>C

Variant summary

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

The NM_002571.4(PAEP):​c.388A>C​(p.Thr130Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,088 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 (★). Synonymous variant affecting the same amino acid position (i.e. T130T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PAEP NM_002571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.69
• 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: 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=0.052331954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAEP	NM_002571.4	c.388A>C	p.Thr130Pro	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.388A>C	p.Thr130Pro	missense_variant	Exon 4 of 7	1	NM_002571.4	ENSP00000417898.1
PAEP	ENST00000371766.6	c.388A>C	p.Thr130Pro	missense_variant	Exon 4 of 7	1		ENSP00000360831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 158338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399088 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31672

American (AMR) AF: 0.00 AC: 0 AN: 35724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35880

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4740

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1079340

Other (OTH) AF: 0.00 AC: 0 AN: 57970

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.003830), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388A>C (p.T130P) alteration is located in exon 4 (coding exon 4) of the PAEP gene. This alteration results from a A to C substitution at nucleotide position 388, causing the threonine (T) at amino acid position 130 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.0070
DANN	Benign	0.17
DEOGEN2	Benign	0.058	T;T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.29	.;.;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;N;N;.
PhyloP100		-1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.15	N;N;N;N
REVEL	Benign	0.057
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.35	T;T;T;T
Polyphen		0.0040	B;B;B;.
Vest4		0.082
MutPred		0.29		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.067
MPC		0.34
ClinPred		0.12	T
GERP RS		-3.6
Varity_R		0.29
gMVP		0.69
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1350535956; hg19: chr9-138456167;