dbSNP rs11571222: PGR:p.Leu651Val (chr11-101062708-G-C) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000926.4(PGR):c.1951C>G(p.Leu651Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,613,656 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 7 hom. )

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.15

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074652135).

BP6

Variant 11-101062708-G-C is Benign according to our data. Variant chr11-101062708-G-C is described in ClinVar as [Benign]. Clinvar id is 720193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1951C>G	p.Leu651Val	missense_variant	Exon 4 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.1951C>G	p.Leu651Val	missense_variant	Exon 4 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

AF:

0.00203

AC:

309

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

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:

0.0116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00235

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00240

AC:

599

AN:

249450

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.000618

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.00301

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00227

AC:

3319

AN:

1461458

Hom.:

Cov.:

AF XY:

0.00217

AC XY:

1578

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33464

American (AMR)

AF:

0.000134

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.0117

AC:

626

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00231

AC:

2571

AN:

1111794

Other (OTH)

AF:

0.00156

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152198

Hom.:

Cov.:

AF XY:

0.00246

AC XY:

183

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000530

AC:

AN:

41546

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0116

AC:

123

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00235

AC:

160

AN:

68002

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00225

Hom.:

Bravo

AF:

0.00129

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00259

AC:

314

EpiCase

AF:

0.00240

EpiControl

AF:

0.00184

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 07, 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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.;.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.85

T;T;T;D

MetaRNN

Benign

0.0075

T;T;T;T

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

1.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.5

N;N;.;.

REVEL

Benign

0.21

Sift

Benign

0.059

T;T;.;.

Sift4G

Benign

0.30

T;T;D;.

Polyphen

0.61

P;.;.;.

Vest4

0.17

MVP

0.74

ClinPred

0.015

GERP RS

1.9

Varity_R

0.066

gMVP

0.29

Mutation Taster

=100/0

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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rs11571222

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