11-101062681-C-G

Position:

• chr11-101062681-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000926.4(PGR):​c.1978G>C​(p.Val660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12899813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGR	NM_000926.4	c.1978G>C	p.Val660Leu	missense_variant	4/8	ENST00000325455.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGR	ENST00000325455.10	c.1978G>C	p.Val660Leu	missense_variant	4/8	1	NM_000926.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250006 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135084

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.59	T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.13	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.6	L;.;.;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.12	T;T;.;.
Sift4G	Benign	0.34	T;T;T;.
Polyphen		0.0060	B;.;.;.
Vest4		0.10
MutPred		0.10		Gain of disorder (P = 0.1557);.;.;.;
MVP		0.73
ClinPred		0.074	T
GERP RS		4.5
Varity_R		0.071
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042838; hg19: chr11-100933412;