Genetic Variant NM_000926.4:c.2488+85T>A (chr11-101049844-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000926.4(PGR):c.2488+85T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,080,746 control chromosomes in the GnomAD database, including 33,286 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 5799 hom., cov: 32)

Exomes 𝑓: 0.24 ( 27487 hom. )

Consequence

PGR
NM_000926.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.555

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000926.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PGR	NM_000926.4	MANE Select	c.2488+85T>A	intron	N/A	NP_000917.3	P06401-1
PGR	NM_001202474.3		c.1996+85T>A	intron	N/A	NP_001189403.1	P06401-2
PGR	NM_001271161.2		c.1690+85T>A	intron	N/A	NP_001258090.1	P06401

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PGR	ENST00000325455.10	TSL:1 MANE Select	c.2488+85T>A	intron	N/A	ENSP00000325120.5	P06401-1
PGR	ENST00000263463.9	TSL:1	c.2182+85T>A	intron	N/A	ENSP00000263463.5	P06401-5
PGR	ENST00000526300.5	TSL:1	n.2051+1580T>A	intron	N/A	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41132

AN:

151966

Hom.:

5776

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.259

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.387

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.217

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.237

Gnomad OTH

AF:

0.283

GnomAD4 exome

AF:

0.239

AC:

221669

AN:

928662

Hom.:

27487

AF XY:

0.234

AC XY:

113093

AN XY:

483828

show subpopulations

African (AFR)

AF:

0.344

AC:

7857

AN:

22816

American (AMR)

AF:

0.261

AC:

10930

AN:

41890

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

8410

AN:

22138

East Asian (EAS)

AF:

0.222

AC:

8006

AN:

35996

South Asian (SAS)

AF:

0.129

AC:

9514

AN:

73510

European-Finnish (FIN)

AF:

0.220

AC:

9943

AN:

45134

Middle Eastern (MID)

AF:

0.233

AC:

961

AN:

4118

European-Non Finnish (NFE)

AF:

0.242

AC:

155111

AN:

640988

Other (OTH)

AF:

0.260

AC:

10937

AN:

42072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

8294

16587

24881

33174

41468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4066

8132

12198

16264

20330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.271

AC:

41216

AN:

152084

Hom.:

5799

Cov.:

AF XY:

0.266

AC XY:

19748

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.349

AC:

14463

AN:

41488

American (AMR)

AF:

0.281

AC:

4283

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.387

AC:

1342

AN:

3472

East Asian (EAS)

AF:

0.226

AC:

1169

AN:

5182

South Asian (SAS)

AF:

0.128

AC:

618

AN:

4826

European-Finnish (FIN)

AF:

0.217

AC:

2295

AN:

10594

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.237

AC:

16133

AN:

67958

Other (OTH)

AF:

0.284

AC:

599

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1532

3063

4595

6126

7658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

414

828

1242

1656

2070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.147

Hom.:

257

Bravo

AF:

0.282

Asia WGS

AF:

0.191

AC:

665

AN:

3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.4

(source)

DANN

Benign

0.68

PhyloP100

0.56

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over