Genetic Variant NM_000926.4:c.1472C>A (chr11-101127599-G-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000926.4(PGR):c.1472C>A(p.Pro491Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,151,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. P491R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000052 ( 0 hom. )

Consequence

PGR
NM_000926.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.38

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3003891).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4 link	c.1472C>A	p.Pro491Gln	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.1472C>A	p.Pro491Gln	missense_variant	Exon 1 of 8	1	NM_000926.4	ENSP00000325120.5		P06401-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000521

AC:

AN:

1151184

Hom.:

Cov.:

AF XY:

0.00000721

AC XY:

AN XY:

554560

show subpopulations

African (AFR)

AF:

0.0000862

AC:

AN:

23192

American (AMR)

AF:

0.00

AC:

AN:

9032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15400

East Asian (EAS)

AF:

0.00

AC:

AN:

26944

South Asian (SAS)

AF:

0.00

AC:

AN:

34156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

966740

Other (OTH)

AF:

0.0000853

AC:

AN:

46898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

T;.;T;.

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.074

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;M;.;.

PhyloP100

2.4

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-1.3

N;N;.;.

REVEL

Benign

0.10

Sift

Benign

0.095

T;T;.;.

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.47

P;.;.;.

Vest4

0.19

MutPred

0.73

Loss of phosphorylation at S486 (P = 0.1191);Loss of phosphorylation at S486 (P = 0.1191);Loss of phosphorylation at S486 (P = 0.1191);Loss of phosphorylation at S486 (P = 0.1191);

MVP

0.57

ClinPred

0.65

GERP RS

3.2

Varity_R

0.061

gMVP

0.31

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

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NM_000926.4:c.1472C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over