chr11-101125999-G-A

Variant names:

• chr11-101125999-G-A
• rs2020875
• NM_000926.4:c.1789+8C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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]

ACMG classification

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1453 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4	c.1789+8C>T		splice_region_variant, intron_variant	Intron 2 of 7	ENST00000325455.10	NP_000917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10	c.1789+8C>T		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_000926.4	ENSP00000325120.5

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

GnomAD2 exomes AF: 0.00954 AC: 2398 AN: 251414 AF XY: 0.00977

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 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

African (AFR) AF: 0.00254 AC: 85 AN: 33470

American (AMR) AF: 0.00557 AC: 249 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26126

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39674

South Asian (SAS) AF: 0.00554 AC: 478 AN: 86234

European-Finnish (FIN) AF: 0.00455 AC: 243 AN: 53406

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.0195 AC: 21714 AN: 1110956

Other (OTH) AF: 0.0146 AC: 883 AN: 60342

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

African (AFR) AF: 0.00284 AC: 118 AN: 41534

American (AMR) AF: 0.00608 AC: 93 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4816

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1163 AN: 68004

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.0127 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

Aug 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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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
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2020875; hg19: chr11-100996730; COSMIC: COSV106391632; COSMIC: COSV106391632;