11-101091797-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_000926.4(PGR):c.1869C>A(p.Arg623=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,607,146 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (103 hom.)
• Consequence: PGR NM_000926.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 11-101091797-G-T is Benign according to our data. Variant chr11-101091797-G-T is described in ClinVar as [Benign]. Clinvar id is 771450.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.19 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00768 (1169/152262) while in subpopulation AMR AF= 0.0331 (506/15298). AF 95% confidence interval is 0.0307. There are 18 homozygotes in gnomad4. There are 751 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1869C>A	p.Arg623=	synonymous_variant	3/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1869C>A	p.Arg623=	synonymous_variant	3/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152146 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0119 AC: 2989 AN: 251188 Hom.: 60 AF XY: 0.00993 AC XY: 1348 AN XY: 135770

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0500

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00240

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0360

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00369 AC: 5368 AN: 1454884 Hom.: 103 Cov.: 29 AF XY: 0.00341 AC XY: 2472 AN XY: 724368

Gnomad4 AFR exome AF: 0.000270

Gnomad4 AMR exome AF: 0.0465

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00590

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0333

Gnomad4 NFE exome AF: 0.000398

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.00768 AC: 1169 AN: 152262 Hom.: 18 Cov.: 33 AF XY: 0.0101 AC XY: 751 AN XY: 74434

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.0331

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.00599

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.0420

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00318 Hom.: 3

Bravo AF: 0.00699

Asia WGS AF: 0.00664 AC: 23 AN: 3478

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

Aug 04, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	7.6
Dann	Benign	0.79

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: rs2020876; hg19: chr11-100962528;