rs1042838

chr11-101062681-C-Achr11-101062681-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000926.4(PGR):c.1978G>T(p.Val660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,600 control chromosomes in the GnomAD database, including 19,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1324 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17838 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015742183).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1978G>T	p.Val660Leu	missense_variant	4/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1978G>T	p.Val660Leu	missense_variant	4/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17607 AN: 152036 Hom.: 1325 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.133

GnomAD3 exomes AF: 0.130 AC: 32533 AN: 250006 Hom.: 2561 AF XY: 0.130 AC XY: 17615 AN XY: 135084

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.0110

Gnomad SAS exome AF: 0.0807

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.151 AC: 220053 AN: 1461446 Hom.: 17838 Cov.: 33 AF XY: 0.148 AC XY: 107783 AN XY: 727032

Gnomad4 AFR exome AF: 0.0229

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.0102

Gnomad4 SAS exome AF: 0.0812

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.116 AC: 17607 AN: 152154 Hom.: 1324 Cov.: 32 AF XY: 0.114 AC XY: 8469 AN XY: 74368

Gnomad4 AFR AF: 0.0300

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.250

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.0738

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.133

Alfa AF: 0.151 Hom.: 4644

Bravo AF: 0.111

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.148 AC: 570

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.164 AC: 1414

ExAC AF: 0.125 AC: 15211

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.163

EpiControl AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.59	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	0.99	P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N;N;.;.
REVEL	Benign	0.21
Sift	Benign	0.12	T;T;.;.
Sift4G	Benign	0.34	T;T;T;.
Polyphen		0.0060	B;.;.;.
Vest4		0.10
MutPred		0.10		Gain of disorder (P = 0.1557);.;.;.;
ClinPred		0.0034	T
GERP RS		4.5
Varity_R		0.071
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042838; hg19: chr11-100933412;