rs1183219530

Variant names:

• chr9-135564341-G-A
• rs1183219530
• NM_002571.4:c.408G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002571.4(PAEP):​c.408G>A​(p.Met136Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAEP NM_002571.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.539
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12899229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAEP	NM_002571.4	c.408G>A	p.Met136Ile	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.408G>A	p.Met136Ile	missense_variant	Exon 4 of 7	1	NM_002571.4	ENSP00000417898.1
PAEP	ENST00000371766.6	c.408G>A	p.Met136Ile	missense_variant	Exon 4 of 7	1		ENSP00000360831.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000637 AC: 1 AN: 156970 AF XY: 0.0000121

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: 0.0000164

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398248 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689672

African (AFR) AF: 0.00 AC: 0 AN: 31586

American (AMR) AF: 0.00 AC: 0 AN: 35704

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35776

South Asian (SAS) AF: 0.00 AC: 0 AN: 79162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4482

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1079116

Other (OTH) AF: 0.0000345 AC: 2 AN: 57920

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.408G>A (p.M136I) alteration is located in exon 4 (coding exon 4) of the PAEP gene. This alteration results from a G to A substitution at nucleotide position 408, causing the methionine (M) at amino acid position 136 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	Pathogenic	0.68
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.7
DANN	Benign	0.67
DEOGEN2	Benign	0.079	T;T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.45	.;.;T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;L;L;.
PhyloP100		-0.54
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.29	N;N;N;N
REVEL	Benign	0.088
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.47	T;T;T;T
Polyphen		0.77	P;P;P;.
Vest4		0.13
MutPred		0.47		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;
MVP		0.13
MPC		0.65
ClinPred		0.063	T
GERP RS		-3.6
Varity_R		0.19
gMVP		0.37
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1183219530; hg19: chr9-138456187;