chr11-101062658-T-G

Variant names:

• chr11-101062658-T-G
• rs1050425959
• NM_000926.4:c.2001A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000926.4(PGR):​c.2001A>C​(p.Gln667His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.475
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGR	NM_000926.4	c.2001A>C	p.Gln667His	missense_variant	Exon 4 of 8	ENST00000325455.10	NP_000917.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGR	ENST00000325455.10	c.2001A>C	p.Gln667His	missense_variant	Exon 4 of 8	1	NM_000926.4	ENSP00000325120.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2001A>C (p.Q667H) alteration is located in exon 4 (coding exon 4) of the PGR gene. This alteration results from a A to C substitution at nucleotide position 2001, causing the glutamine (Q) at amino acid position 667 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;.;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.068
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Uncertain	-0.015	T
MutationAssessor	Uncertain	2.6	M;.;.;.
PhyloP100		-0.47
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.5	D;D;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	D;T;.;.
Sift4G	Benign	0.062	T;T;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.20
MutPred		0.33		Gain of catalytic residue at L669 (P = 0.0876);.;.;.;
MVP		0.91
ClinPred		0.81	D
GERP RS		0.95
Varity_R		0.17
gMVP		0.54
Mutation Taster		=70/30	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: rs1050425959; hg19: chr11-100933389;