11-101127591-C-T

Variant names:

• chr11-101127591-C-T
• rs767987713
• NM_000926.4:c.1480G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000926.4(PGR):​c.1480G>A​(p.Gly494Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 1,311,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.927
• Publications: 3 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033022642).

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.1480G>A	p.Gly494Ser	missense	Exon 1 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.988G>A	p.Gly330Ser	missense	Exon 1 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.988G>A	p.Gly330Ser	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.1480G>A	p.Gly494Ser	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1480G>A	p.Gly494Ser	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.1480G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151512 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1159522 Hom.: 0 Cov.: 30 AF XY: 0.00000179 AC XY: 1 AN XY: 559772

African (AFR) AF: 0.00 AC: 0 AN: 23386

American (AMR) AF: 0.00 AC: 0 AN: 9500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15700

East Asian (EAS) AF: 0.00 AC: 0 AN: 26964

South Asian (SAS) AF: 0.00 AC: 0 AN: 36240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3726

European-Non Finnish (NFE) AF: 0.00000206 AC: 2 AN: 971030

Other (OTH) AF: 0.00 AC: 0 AN: 47282

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151512 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74032

African (AFR) AF: 0.0000242 AC: 1 AN: 41344

American (AMR) AF: 0.0000657 AC: 1 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67832

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.059
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.4
DANN	Benign	0.96
DEOGEN2	Benign	0.046	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.93
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.55	N
REVEL	Benign	0.010
Sift	Benign	0.94	T
Sift4G	Benign	0.50	T
Polyphen		0.031	B
Vest4		0.036
MutPred		0.37		Gain of glycosylation at G494 (P = 0.0018)
MVP		0.41
ClinPred		0.051	T
GERP RS		-4.5
Varity_R		0.023
gMVP		0.21
Mutation Taster		=94/6	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: rs767987713; hg19: chr11-100998322;