11-101051458-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000926.4(PGR):c.2323A>G(p.Met775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.2323A>G	p.Met775Val	missense_variant	5/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.2323A>G	p.Met775Val	missense_variant	5/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457880 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.2323A>G (p.M775V) alteration is located in exon 5 (coding exon 5) of the PGR gene. This alteration results from a A to G substitution at nucleotide position 2323, causing the methionine (M) at amino acid position 775 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T;D;T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.9	L;.;.;.;.
MutationTaster	Benign	0.97	D;D;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.8	D;D;D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0060	D;D;D;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.98	D;.;.;.;.
Vest4		0.44
MutPred		0.65		Loss of catalytic residue at V771 (P = 0.0338);.;.;.;.;
MVP		0.87
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.67
gMVP		0.47

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-100922189;