11-101127464-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000926.4(PGR):c.1607A>C(p.Gln536Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00093 in 1,560,306 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0047 (9 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (7 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.863

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048434734).
• BP6: Variant 11-101127464-T-G is Benign according to our data. Variant chr11-101127464-T-G is described in ClinVar as [Benign]. Clinvar id is 716972.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000525 (740/1408222) while in subpopulation AFR AF= 0.0175 (516/29478). AF 95% confidence interval is 0.0163. There are 7 homozygotes in gnomad4_exome. There are 329 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 710 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1607A>C	p.Gln536Pro	missense_variant	1/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1607A>C	p.Gln536Pro	missense_variant	1/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 710 AN: 151976 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

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: 0.0000736

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000876 AC: 143 AN: 163246 Hom.: 2 AF XY: 0.000747 AC XY: 68 AN XY: 91082

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.000127

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000525 AC: 740 AN: 1408222 Hom.: 7 Cov.: 31 AF XY: 0.000471 AC XY: 329 AN XY: 698036

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000999

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00468 AC: 711 AN: 152084 Hom.: 9 Cov.: 33 AF XY: 0.00455 AC XY: 338 AN XY: 74356

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000648 Hom.: 0

Bravo AF: 0.00578

ESP6500AA AF: 0.00909 AC: 31

ESP6500EA AF: 0.000280 AC: 2

ExAC AF: 0.00103 AC: 117

Asia WGS AF: 0.00116 AC: 4 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.11	T;.;T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.70	T;T;T;T
MetaRNN	Benign	0.0048	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;.;.
MutationTaster	Benign	0.97	D;D;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;.;.
REVEL	Benign	0.043
Sift	Benign	0.092	T;T;.;.
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.055	B;.;.;.
Vest4		0.25
MVP		0.40
ClinPred		0.021	T
GERP RS		2.9
Varity_R		0.35
gMVP		0.58

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: rs11571152; hg19: chr11-100998195;