chr11-101127464-T-G

Variant names:

• chr11-101127464-T-G
• rs11571152
• NM_000926.4:c.1607A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.863
• Publications: 4 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]

PGR-AS1 (HGNC:52650): (PGR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 716972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 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 GnomAdExome4. There are 329 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 711 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000926.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGR	NM_000926.4	MANE Select	c.1607A>C	p.Gln536Pro	missense	Exon 1 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.1115A>C	p.Gln372Pro	missense	Exon 1 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.1115A>C	p.Gln372Pro	missense	Exon 1 of 7	NP_001258090.1	P06401

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGR	ENST00000325455.10	TSL:1 MANE Select	c.1607A>C	p.Gln536Pro	missense	Exon 1 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1607A>C	p.Gln536Pro	missense	Exon 1 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.1607A>C		non_coding_transcript_exon	Exon 1 of 6	ENSP00000436803.1	Q8NG45

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

GnomAD2 exomes AF: 0.000876 AC: 143 AN: 163246 AF XY: 0.000747

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 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

African (AFR) AF: 0.0175 AC: 516 AN: 29478

American (AMR) AF: 0.00131 AC: 51 AN: 38994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24640

East Asian (EAS) AF: 0.00 AC: 0 AN: 34892

South Asian (SAS) AF: 0.0000999 AC: 8 AN: 80076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48596

Middle Eastern (MID) AF: 0.00115 AC: 6 AN: 5216

European-Non Finnish (NFE) AF: 0.0000441 AC: 48 AN: 1088176

Other (OTH) AF: 0.00191 AC: 111 AN: 58154

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

African (AFR) AF: 0.0159 AC: 659 AN: 41524

American (AMR) AF: 0.00281 AC: 43 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5102

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67954

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000668 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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.86
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.043
Sift	Benign	0.092	T
Sift4G	Benign	0.25	T
Polyphen		0.055	B
Vest4		0.25
MVP		0.40
ClinPred		0.021	T
GERP RS		2.9
PromoterAI		0.053	Neutral
Varity_R		0.35
gMVP		0.58
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs11571152; hg19: chr11-100998195;