11-101125999-G-A

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.1789+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,612,912 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0095 (10 hom., cov: 33)
  • Exomes 𝑓: 0.016 (231 hom.)
• Consequence: PGR NM_000926.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001037
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0110

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 (BayesDel_noAF=-0.82).
• BP6: Variant 11-101125999-G-A is Benign according to our data. Variant chr11-101125999-G-A is described in ClinVar as [Benign]. Clinvar id is 785890.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00955 (1453/152218) while in subpopulation NFE AF= 0.0171 (1163/68004). AF 95% confidence interval is 0.0163. There are 10 homozygotes in gnomad4. There are 616 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 1452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1789+8C>T		splice_region_variant, intron_variant		ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1789+8C>T		splice_region_variant, intron_variant		1	NM_000926.4	P1

Frequencies

GnomAD3 genomes AF: 0.00955 AC: 1452 AN: 152100 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00954 AC: 2398 AN: 251414 Hom.: 19 AF XY: 0.00977 AC XY: 1328 AN XY: 135898

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00503

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.0164

Gnomad OTH exome AF: 0.00879

GnomAD4 exome AF: 0.0162 AC: 23676 AN: 1460694 Hom.: 231 Cov.: 31 AF XY: 0.0159 AC XY: 11587 AN XY: 726728

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00554

Gnomad4 FIN exome AF: 0.00455

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0146

GnomAD4 genome AF: 0.00955 AC: 1453 AN: 152218 Hom.: 10 Cov.: 33 AF XY: 0.00828 AC XY: 616 AN XY: 74422

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.0171

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.0133 Hom.: 7

Bravo AF: 0.00961

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0139

EpiControl AF: 0.0156

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 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.9
Dann	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
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: rs2020875; hg19: chr11-100996730;