9-135561828-C-T

Variant names:

• chr9-135561828-C-T
• rs6537900
• NM_002571.4:c.27C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002571.4(PAEP):​c.27C>T​(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,558,280 control chromosomes in the GnomAD database, including 82 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (43 hom.)
• Consequence: PAEP NM_002571.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.125
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-135561828-C-T is Benign according to our data. Variant chr9-135561828-C-T is described in ClinVar as [Benign]. Clinvar id is 781189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.125 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1901/152286) while in subpopulation AFR AF = 0.044 (1828/41562). AF 95% confidence interval is 0.0423. There are 39 homozygotes in GnomAd4. There are 882 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAEP	NM_002571.4	c.27C>T	p.Gly9Gly	synonymous_variant	Exon 1 of 7	ENST00000479141.6	NP_002562.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAEP	ENST00000479141.6	c.27C>T	p.Gly9Gly	synonymous_variant	Exon 1 of 7	1	NM_002571.4	ENSP00000417898.1
PAEP	ENST00000371766.6	c.27C>T	p.Gly9Gly	synonymous_variant	Exon 1 of 7	1		ENSP00000360831.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1898 AN: 152168 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00264 AC: 440 AN: 166650 AF XY: 0.00198

Gnomad AFR exome AF: 0.0427

Gnomad AMR exome AF: 0.000731

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000302

Gnomad OTH exome AF: 0.00175

GnomAD4 exome AF: 0.00123 AC: 1723 AN: 1405994 Hom.: 43 Cov.: 32 AF XY: 0.00106 AC XY: 734 AN XY: 694110

African (AFR) AF: 0.0474 AC: 1521 AN: 32088

American (AMR) AF: 0.00108 AC: 40 AN: 36946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25242

East Asian (EAS) AF: 0.00 AC: 0 AN: 36580

South Asian (SAS) AF: 0.0000878 AC: 7 AN: 79764

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 49054

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5694

European-Non Finnish (NFE) AF: 0.0000176 AC: 19 AN: 1082408

Other (OTH) AF: 0.00223 AC: 130 AN: 58218

GnomAD4 genome AF: 0.0125 AC: 1901 AN: 152286 Hom.: 39 Cov.: 33 AF XY: 0.0118 AC XY: 882 AN XY: 74450

African (AFR) AF: 0.0440 AC: 1828 AN: 41562

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00720 Hom.: 8

Bravo AF: 0.0140

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.8
DANN	Benign	0.80
PhyloP100		0.13
PromoterAI		0.059	Neutral
Mutation Taster		=100/0	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: rs6537900; hg19: chr9-138453674;