11-101127564-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000926.4(PGR):c.1507G>A(p.Ala503Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000396 in 151,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0830

Publications

3 publications found

Variant links:

Genes affected

PGR (HGNC:8910): (progesterone receptor) This gene encodes a member of the steroid receptor superfamily. The encoded protein mediates the physiological effects of progesterone, which plays a central role in reproductive events associated with the establishment and maintenance of pregnancy. This gene uses two distinct promotors and translation start sites in the first exon to produce several transcript variants, both protein coding and non-protein coding. Two of the isoforms (A and B) are identical except for an additional 165 amino acids found in the N-terminus of isoform B and mediate their own response genes and physiologic effects with little overlap. [provided by RefSeq, Sep 2015]

PGR links:

PGR-AS1 (HGNC:52650): (PGR antisense RNA 1)

PGR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15797713).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1507G>A	p.Ala503Thr	missense_variant	Exon 1 of 8	ENST00000325455.10	NP_000917.3	P06401-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10 link	c.1507G>A	p.Ala503Thr	missense_variant	Exon 1 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000164

AC:

AN:

1221690

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

596962

show subpopulations

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

African (AFR)

AF:

0.0000393

AC:

AN:

25438

American (AMR)

AF:

0.00

AC:

AN:

19528

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19608

East Asian (EAS)

AF:

0.00

AC:

AN:

27340

South Asian (SAS)

AF:

0.00

AC:

AN:

51916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29824

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3876

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

994612

Other (OTH)

AF:

0.0000202

AC:

AN:

49548

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151534

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74010

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41302

American (AMR)

AF:

0.00

AC:

AN:

15222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5104

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67826

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1507G>A (p.A503T) alteration is located in exon 1 (coding exon 1) of the PGR gene. This alteration results from a G to A substitution at nucleotide position 1507, causing the alanine (A) at amino acid position 503 to be replaced by a threonine (T). 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

0.092

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.066

T;.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.53

T;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.76

N;N;.;.

PhyloP100

-0.083

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.18

N;N;.;.

REVEL

Benign

0.036

Sift

Benign

0.23

T;T;.;.

Sift4G

Benign

0.31

T;T;T;T

Polyphen

0.035

B;.;.;.

Vest4

0.16

MutPred

0.50

Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);Gain of glycosylation at A503 (P = 0.0032);

MVP

0.52

ClinPred

0.48

GERP RS

-0.27

PromoterAI

-0.083

Neutral

(source)

Varity_R

0.043

gMVP

0.32

Mutation Taster

=94/6

polymorphism

(source)

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

Publications

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11-101127564-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over