Genetic Variant PGR:p.Arg623Arg (chr11-101091797-G-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000926.4(PGR):c.1869C>A(p.Arg623Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,607,146 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 18 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 103 hom. )

Consequence

PGR
NM_000926.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.19

Publications

6 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant 11-101091797-G-T is Benign according to our data. Variant chr11-101091797-G-T is described in ClinVar as [Benign]. Clinvar id is 771450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.19 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00768 (1169/152262) while in subpopulation AMR AF = 0.0331 (506/15298). AF 95% confidence interval is 0.0307. There are 18 homozygotes in GnomAd4. There are 751 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1869C>A	p.Arg623Arg	synonymous_variant	Exon 3 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.1869C>A	p.Arg623Arg	synonymous_variant	Exon 3 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

AF:

0.00766

AC:

1165

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0329

Gnomad ASJ

AF:

0.0216

Gnomad EAS

AF:

0.00598

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0420

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000970

Gnomad OTH

AF:

0.00812

GnomAD2 exomes

AF:

0.0119

AC:

2989

AN:

251188

AF XY:

0.00993

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0500

Gnomad ASJ exome

AF:

0.0201

Gnomad EAS exome

AF:

0.00240

Gnomad FIN exome

AF:

0.0360

Gnomad NFE exome

AF:

0.00144

Gnomad OTH exome

AF:

0.00898

GnomAD4 exome

AF:

0.00369

AC:

5368

AN:

1454884

Hom.:

103

Cov.:

AF XY:

0.00341

AC XY:

2472

AN XY:

724368

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33342

American (AMR)

AF:

0.0465

AC:

2080

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

533

AN:

26096

East Asian (EAS)

AF:

0.00590

AC:

234

AN:

39654

South Asian (SAS)

AF:

0.000313

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.0333

AC:

1777

AN:

53364

Middle Eastern (MID)

AF:

0.000522

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000398

AC:

440

AN:

1105686

Other (OTH)

AF:

0.00441

AC:

265

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

302

604

906

1208

1510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00768

AC:

1169

AN:

152262

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

751

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41558

American (AMR)

AF:

0.0331

AC:

506

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0216

AC:

AN:

3472

East Asian (EAS)

AF:

0.00599

AC:

AN:

5172

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0420

AC:

445

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000970

AC:

AN:

68020

Other (OTH)

AF:

0.00803

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00322

Hom.:

Bravo

AF:

0.00699

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.6

(source)

DANN

Benign

0.79

PhyloP100

2.2

Mutation Taster

=88/12

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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chr11-101091797-G-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