11-101127627-C-T

Variant names:

• chr11-101127627-C-T
• rs1049123163
• NM_000926.4:c.1444G>A

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.1444G>A​(p.Ala482Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000673 in 1,336,340 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.139
• 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=0.09388104).
• BS2: High AC in GnomAd4 at 5 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.1444G>A	p.Ala482Thr	missense	Exon 1 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.952G>A	p.Ala318Thr	missense	Exon 1 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.952G>A	p.Ala318Thr	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.1444G>A	p.Ala482Thr	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1444G>A	p.Ala482Thr	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.1444G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151306 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

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: 0.00000338 AC: 4 AN: 1184926 Hom.: 0 Cov.: 31 AF XY: 0.00000348 AC XY: 2 AN XY: 574024

African (AFR) AF: 0.00 AC: 0 AN: 23910

American (AMR) AF: 0.000185 AC: 2 AN: 10786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16964

East Asian (EAS) AF: 0.00 AC: 0 AN: 27400

South Asian (SAS) AF: 0.00 AC: 0 AN: 42184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4280

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 984316

Other (OTH) AF: 0.00 AC: 0 AN: 48428

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151414 Hom.: 0 Cov.: 33 AF XY: 0.0000541 AC XY: 4 AN XY: 73990

African (AFR) AF: 0.0000241 AC: 1 AN: 41426

American (AMR) AF: 0.000263 AC: 4 AN: 15182

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5062

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67812

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000567

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	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.14
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.048
Sift	Benign	0.11	T
Sift4G	Benign	0.48	T
Polyphen		0.32	B
Vest4		0.12
MutPred		0.34		Gain of glycosylation at A482 (P = 0.006)
MVP		0.32
ClinPred		0.29	T
GERP RS		3.2
Varity_R		0.045
gMVP		0.28
Mutation Taster		=90/10	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: rs1049123163; hg19: chr11-100998358;