NM_000926.4:c.1184A>G

Variant names:

• chr11-101127887-T-C
• rs748524564
• NM_000926.4:c.1184A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000926.4(PGR):​c.1184A>G​(p.Glu395Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,588,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E395A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96
• Publications: 1 publications found

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-AS1 (HGNC:52650): (PGR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25272626).
• BS2: High AC in GnomAdExome4 at 36 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGR	NM_000926.4	MANE Select	c.1184A>G	p.Glu395Gly	missense	Exon 1 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.692A>G	p.Glu231Gly	missense	Exon 1 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.692A>G	p.Glu231Gly	missense	Exon 1 of 7	NP_001258090.1	P06401

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGR	ENST00000325455.10	TSL:1 MANE Select	c.1184A>G	p.Glu395Gly	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1184A>G	p.Glu395Gly	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.1184A>G		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes AF: 0.00000673 AC: 1 AN: 148618 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000131 AC: 3 AN: 228298 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000296

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000250 AC: 36 AN: 1439384 Hom.: 0 Cov.: 32 AF XY: 0.0000265 AC XY: 19 AN XY: 716950

African (AFR) AF: 0.00 AC: 0 AN: 32376

American (AMR) AF: 0.00 AC: 0 AN: 43856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 37194

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000317 AC: 35 AN: 1103180

Other (OTH) AF: 0.00 AC: 0 AN: 58834

GnomAD4 genome AF: 0.00000672 AC: 1 AN: 148758 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 1 AN XY: 72724

African (AFR) AF: 0.00 AC: 0 AN: 40308

American (AMR) AF: 0.00 AC: 0 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4668

South Asian (SAS) AF: 0.00 AC: 0 AN: 4526

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 264

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67128

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000252 AC: 3

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.066
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.088	T
Polyphen		0.64	P
Vest4		0.18
MutPred		0.42		Gain of loop (P = 0.0312)
MVP		0.24
ClinPred		0.79	D
GERP RS		2.8
Varity_R		0.12
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs748524564; hg19: chr11-100998618;