11-101128031-C-G

Position:

• chr11-101128031-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000325455.10(PGR):​c.1040G>C​(p.Cys347Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00512 in 1,607,940 control chromosomes in the GnomAD database, including 351 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.028 (179 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (172 hom.)
• Consequence: PGR ENST00000325455.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.19

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016167462).
• BP6: Variant 11-101128031-C-G is Benign according to our data. Variant chr11-101128031-C-G is described in ClinVar as [Benign]. Clinvar id is 768473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0944 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGR	NM_000926.4	c.1040G>C	p.Cys347Ser	missense_variant	1/8	ENST00000325455.10	NP_000917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10	c.1040G>C	p.Cys347Ser	missense_variant	1/8	1	NM_000926.4	ENSP00000325120	P1

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4179 AN: 152104 Hom.: 177 Cov.: 33

Gnomad AFR AF: 0.0970

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0210

GnomAD3 exomes AF: 0.00657 AC: 1542 AN: 234720 Hom.: 67 AF XY: 0.00480 AC XY: 623 AN XY: 129792

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000171

Gnomad OTH exome AF: 0.00154

GnomAD4 exome AF: 0.00278 AC: 4052 AN: 1455718 Hom.: 172 Cov.: 37 AF XY: 0.00238 AC XY: 1721 AN XY: 724488

Gnomad4 AFR exome AF: 0.100

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000124

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.0275 AC: 4187 AN: 152222 Hom.: 179 Cov.: 33 AF XY: 0.0263 AC XY: 1958 AN XY: 74414

Gnomad4 AFR AF: 0.0969

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.00884 Hom.: 16

Bravo AF: 0.0311

ESP6500AA AF: 0.0795 AC: 334

ESP6500EA AF: 0.000359 AC: 3

ExAC AF: 0.00789 AC: 946

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.63
DEOGEN2	Benign	0.044	T;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.32	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N;N;.;.
MutationTaster	Benign	0.99	D;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	1.4	N;N;.;.
REVEL	Benign	0.065
Sift	Benign	1.0	T;T;.;.
Sift4G	Benign	0.58	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.074
MutPred		0.15		Gain of glycosylation at C347 (P = 0.0049);Gain of glycosylation at C347 (P = 0.0049);Gain of glycosylation at C347 (P = 0.0049);Gain of glycosylation at C347 (P = 0.0049);
MVP		0.13
ClinPred		0.0025	T
GERP RS		3.7
Varity_R		0.075
gMVP		0.12

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: rs11571147; hg19: chr11-100998762;