11-101128040-C-G

Variant names:

• chr11-101128040-C-G
• rs3740753
• NM_000926.4:c.1031G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000926.4(PGR):​c.1031G>C​(p.Ser344Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,605,944 control chromosomes in the GnomAD database, including 19,352 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1366 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17986 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.632
• Publications: 29 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019226074).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4	c.1031G>C	p.Ser344Thr	missense_variant	Exon 1 of 8	ENST00000325455.10	NP_000917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10	c.1031G>C	p.Ser344Thr	missense_variant	Exon 1 of 8	1	NM_000926.4	ENSP00000325120.5

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17840 AN: 152008 Hom.: 1367 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.0801

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.134

GnomAD2 exomes AF: 0.132 AC: 30549 AN: 231704 AF XY: 0.132

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.248

Gnomad EAS exome AF: 0.0107

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.154

GnomAD4 exome AF: 0.152 AC: 220890 AN: 1453818 Hom.: 17986 Cov.: 41 AF XY: 0.150 AC XY: 108320 AN XY: 723640

African (AFR) AF: 0.0231 AC: 773 AN: 33470

American (AMR) AF: 0.146 AC: 6527 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6439 AN: 26096

East Asian (EAS) AF: 0.0107 AC: 426 AN: 39688

South Asian (SAS) AF: 0.0869 AC: 7497 AN: 86234

European-Finnish (FIN) AF: 0.159 AC: 7276 AN: 45820

Middle Eastern (MID) AF: 0.126 AC: 726 AN: 5766

European-Non Finnish (NFE) AF: 0.164 AC: 182195 AN: 1111740

Other (OTH) AF: 0.150 AC: 9031 AN: 60316

GnomAD4 genome AF: 0.117 AC: 17839 AN: 152126 Hom.: 1366 Cov.: 33 AF XY: 0.115 AC XY: 8578 AN XY: 74388

African (AFR) AF: 0.0303 AC: 1259 AN: 41554

American (AMR) AF: 0.138 AC: 2117 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 871 AN: 3470

East Asian (EAS) AF: 0.0118 AC: 60 AN: 5100

South Asian (SAS) AF: 0.0797 AC: 385 AN: 4828

European-Finnish (FIN) AF: 0.157 AC: 1670 AN: 10608

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10924 AN: 67948

Other (OTH) AF: 0.134 AC: 282 AN: 2106

Alfa AF: 0.159 Hom.: 616

Bravo AF: 0.112

TwinsUK AF: 0.158 AC: 586

ALSPAC AF: 0.150 AC: 577

ESP6500AA AF: 0.0255 AC: 106

ESP6500EA AF: 0.150 AC: 1244

ExAC AF: 0.124 AC: 14789

Asia WGS AF: 0.0570 AC: 199 AN: 3478

EpiCase AF: 0.165

EpiControl AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.088	T;.;T;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.64	T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;N;.;.
PhyloP100		0.63
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N;.;.
REVEL	Benign	0.019
Sift	Benign	0.042	D;D;.;.
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.15	B;.;.;.
Vest4		0.10
ClinPred		0.0042	T
GERP RS		1.8
Varity_R		0.13
gMVP		0.12
Mutation Taster		=99/1	polymorphism (auto)

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: rs3740753; hg19: chr11-100998771; COSMIC: COSV54806663; COSMIC: COSV54806663;