Genetic Variant PGR:p.Glu395Val (chr11-101127887-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000926.4(PGR):c.1184A>T(p.Glu395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E395G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

Publications

0 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29530653).

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	HGVSp	Effect	Exon Rank	Protein	UniProt
PGR	NM_000926.4	MANE Select	c.1184A>T	p.Glu395Val	missense	Exon 1 of 8	NP_000917.3	P06401-1
PGR	NM_001202474.3		c.692A>T	p.Glu231Val	missense	Exon 1 of 8	NP_001189403.1	P06401-2
PGR	NM_001271161.2		c.692A>T	p.Glu231Val	missense	Exon 1 of 7	NP_001258090.1	P06401

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGR	ENST00000325455.10	TSL:1 MANE Select	c.1184A>T	p.Glu395Val	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
PGR	ENST00000263463.9	TSL:1	c.1184A>T	p.Glu395Val	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
PGR	ENST00000526300.5	TSL:1	n.1184A>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1439386

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

716952

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

32376

American (AMR)

AF:

0.00

AC:

AN:

43856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25130

East Asian (EAS)

AF:

0.00

AC:

AN:

37194

South Asian (SAS)

AF:

0.00

AC:

AN:

85984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5684

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1103180

Other (OTH)

AF:

0.00

AC:

AN:

58834

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.250

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.30

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

2.0

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.7

REVEL

Benign

0.085

Sift

Uncertain

0.0020

Sift4G

Benign

0.064

Polyphen

0.93

Vest4

0.24

MutPred

0.47

Loss of glycosylation at S397 (P = 0.1112)

MVP

0.35

ClinPred

0.88

GERP RS

2.8

Varity_R

0.24

gMVP

0.40

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over