11-101051471-G-T

Variant names:

• chr11-101051471-G-T
• rs1042839
• NM_000926.4:c.2310C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000926.4(PGR):​c.2310C>A​(p.His770Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.750
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

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.2310C>A	p.His770Gln	missense	Exon 5 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.1818C>A	p.His606Gln	missense	Exon 5 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271161.2		c.1512C>A	p.His504Gln	missense	Exon 4 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.2310C>A	p.His770Gln	missense	Exon 5 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.2004C>A	p.His668Gln	missense	Exon 4 of 7	ENSP00000263463.5	P06401-5
	PGR	ENST00000526300.5	TSL:1	n.2004C>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000436803.1	Q8NG45

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455822 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724642

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106834

Other (OTH) AF: 0.00 AC: 0 AN: 60156

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.2	L
PhyloP100		0.75
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.59
Sift	Benign	0.18	T
Sift4G	Benign	0.12	T
Polyphen		0.79	P
Vest4		0.35
MutPred		0.52		Gain of MoRF binding (P = 0.0806)
MVP		0.85
ClinPred		0.99	D
GERP RS		-0.88
Varity_R		0.54
gMVP		0.50
Mutation Taster		=42/58	disease causing

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: rs1042839; hg19: chr11-100922202;