11-101126118-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000926.4(PGR):c.1678G>A(p.Glu560Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30614835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1678G>A	p.Glu560Lys	missense_variant	2/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1678G>A	p.Glu560Lys	missense_variant	2/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Mar 01, 2024

The c.1678G>A (p.E560K) alteration is located in exon 2 (coding exon 2) of the PGR gene. This alteration results from a G to A substitution at nucleotide position 1678, causing the glutamic acid (E) at amino acid position 560 to be replaced by a lysine (K). 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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;.;.
MutationTaster	Benign	0.96	D;D;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N;N;.;.;.
REVEL	Benign	0.12
Sift	Uncertain	0.020	D;D;.;.;.
Sift4G	Benign	0.35	T;T;T;T;.
Polyphen		0.97	D;.;.;.;.
Vest4		0.24
MutPred		0.49		Gain of methylation at E560 (P = 0.0048);Gain of methylation at E560 (P = 0.0048);Gain of methylation at E560 (P = 0.0048);Gain of methylation at E560 (P = 0.0048);.;
MVP		0.54
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.26
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr11-100996849;