11-101127840-G-T

Variant names:

• chr11-101127840-G-T
• rs1402730866
• NM_000926.4:c.1231C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000926.4(PGR):​c.1231C>A​(p.Pro411Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,585,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P411A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11067444).

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.1231C>A	p.Pro411Thr	missense	Exon 1 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.739C>A	p.Pro247Thr	missense	Exon 1 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.739C>A	p.Pro247Thr	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.1231C>A	p.Pro411Thr	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1231C>A	p.Pro411Thr	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.1231C>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152034 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433460 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712288

African (AFR) AF: 0.00 AC: 0 AN: 33240

American (AMR) AF: 0.00 AC: 0 AN: 41432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25756

East Asian (EAS) AF: 0.00 AC: 0 AN: 38880

South Asian (SAS) AF: 0.00 AC: 0 AN: 84764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39726

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104272

Other (OTH) AF: 0.00 AC: 0 AN: 59650

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.85
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.028
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.021
Sift	Benign	0.065	T
Sift4G	Benign	0.22	T
Polyphen		0.15	B
Vest4		0.14
MutPred		0.58		Gain of phosphorylation at P411 (P = 0.0532)
MVP		0.28
ClinPred		0.093	T
GERP RS		-2.5
Varity_R		0.041
gMVP		0.25
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: rs1402730866; hg19: chr11-100998571; COSMIC: COSV54803066; COSMIC: COSV54803066;