rs1042838

Variant names:

• chr11-101062681-C-A
• rs1042838
• NM_000926.4:c.1978G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-101062681-C-A
• chr11-101062681-C-G
• chr11-101062681-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000926.4(PGR):​c.1978G>T​(p.Val660Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,600 control chromosomes in the GnomAD database, including 19,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1324 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17838 hom.)
• Consequence: PGR NM_000926.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.708
• Publications: 131 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015742183).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

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.1978G>T	p.Val660Leu	missense	Exon 4 of 8	NP_000917.3	P06401-1
	PGR	NM_001202474.3		c.1486G>T	p.Val496Leu	missense	Exon 4 of 8	NP_001189403.1	P06401-2
	PGR	NM_001271162.2		c.196G>T	p.Val66Leu	missense	Exon 4 of 8	NP_001258091.1	P06401-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGR	ENST00000325455.10	TSL:1 MANE Select	c.1978G>T	p.Val660Leu	missense	Exon 4 of 8	ENSP00000325120.5	P06401-1
	PGR	ENST00000263463.9	TSL:1	c.1907-11113G>T		intron	N/A	ENSP00000263463.5	P06401-5
	PGR	ENST00000528960.5	TSL:1	n.1861G>T		non_coding_transcript_exon	Exon 3 of 7	ENSP00000432914.1	Q8NG44

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17607 AN: 152036 Hom.: 1325 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.130 AC: 32533 AN: 250006 AF XY: 0.130

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.246

Gnomad EAS exome AF: 0.0110

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.153

GnomAD4 exome AF: 0.151 AC: 220053 AN: 1461446 Hom.: 17838 Cov.: 33 AF XY: 0.148 AC XY: 107783 AN XY: 727032

African (AFR) AF: 0.0229 AC: 767 AN: 33474

American (AMR) AF: 0.144 AC: 6438 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6427 AN: 26130

East Asian (EAS) AF: 0.0102 AC: 406 AN: 39682

South Asian (SAS) AF: 0.0812 AC: 7000 AN: 86248

European-Finnish (FIN) AF: 0.157 AC: 8405 AN: 53380

Middle Eastern (MID) AF: 0.118 AC: 678 AN: 5766

European-Non Finnish (NFE) AF: 0.163 AC: 180972 AN: 1111694

Other (OTH) AF: 0.148 AC: 8960 AN: 60384

GnomAD4 genome AF: 0.116 AC: 17607 AN: 152154 Hom.: 1324 Cov.: 32 AF XY: 0.114 AC XY: 8469 AN XY: 74368

African (AFR) AF: 0.0300 AC: 1247 AN: 41546

American (AMR) AF: 0.136 AC: 2073 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 866 AN: 3470

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5174

South Asian (SAS) AF: 0.0738 AC: 356 AN: 4824

European-Finnish (FIN) AF: 0.157 AC: 1658 AN: 10554

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.160 AC: 10849 AN: 67992

Other (OTH) AF: 0.133 AC: 281 AN: 2116

Alfa AF: 0.146 Hom.: 7854

Bravo AF: 0.111

TwinsUK AF: 0.158 AC: 585

ALSPAC AF: 0.148 AC: 570

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.164 AC: 1414

ExAC AF: 0.125 AC: 15211

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.163

EpiControl AF: 0.158

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.71
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.21
Sift	Benign	0.12	T
Sift4G	Benign	0.34	T
Polyphen		0.0060	B
Vest4		0.10
MutPred		0.10		Gain of disorder (P = 0.1557)
ClinPred		0.0034	T
GERP RS		4.5
Varity_R		0.071
gMVP		0.17
Mutation Taster		=97/3	polymorphism (auto)

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: rs1042838; hg19: chr11-100933412; COSMIC: COSV107217683;