1-216519327-C-T

Variant names:

• chr1-216519327-C-T
• rs945453
• NM_001438.4:c.957G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001438.4(ESRRG):​c.957G>A​(p.Ser319Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,612,634 control chromosomes in the GnomAD database, including 157,727 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.51 (21315 hom., cov: 32)
  • Exomes 𝑓: 0.42 (136412 hom.)
• Consequence: ESRRG NM_001438.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 23 publications found

Genes affected

ESRRG (HGNC:3474): (estrogen related receptor gamma) This gene encodes a member of the estrogen receptor-related receptor (ESRR) family, which belongs to the nuclear hormone receptor superfamily. All members of the ESRR family share an almost identical DNA binding domain, which is composed of two C4-type zinc finger motifs. The ESRR members are orphan nuclear receptors; they bind to the estrogen response element and steroidogenic factor 1 response element, and activate genes controlled by both response elements in the absence of any ligands. The ESRR family is closely related to the estrogen receptor (ER) family. They share target genes, co-regulators and promoters, and by targeting the same set of genes, the ESRRs seem to interfere with the ER-mediated estrogen response in various ways. It has been reported that the family member encoded by this gene functions as a transcriptional activator of DNA cytosine-5-methyltransferases 1 (Dnmt1) expression by direct binding to its response elements in the DNMT1 promoters, modulates cell proliferation and estrogen signaling in breast cancer, and negatively regulates bone morphogenetic protein 2-induced osteoblast differentiation and bone formation. Multiple alternatively spliced transcript variants have been identified, which mainly differ at the 5' end and some of which encode protein isoforms differing in the N-terminal region. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.957G>A	p.Ser319Ser	synonymous_variant	Exon 6 of 7	ENST00000408911.8	NP_001429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000408911.8	c.957G>A	p.Ser319Ser	synonymous_variant	Exon 6 of 7	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78131 AN: 151920 Hom.: 21288 Cov.: 32

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.516

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.594

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.584

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.602

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.541

GnomAD2 exomes AF: 0.506 AC: 126803 AN: 250762 AF XY: 0.500

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.638

Gnomad ASJ exome AF: 0.600

Gnomad EAS exome AF: 0.721

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.419 AC: 612391 AN: 1460596 Hom.: 136412 Cov.: 36 AF XY: 0.424 AC XY: 308051 AN XY: 726644

African (AFR) AF: 0.682 AC: 22785 AN: 33424

American (AMR) AF: 0.633 AC: 28261 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.603 AC: 15762 AN: 26118

East Asian (EAS) AF: 0.700 AC: 27788 AN: 39688

South Asian (SAS) AF: 0.582 AC: 50217 AN: 86224

European-Finnish (FIN) AF: 0.390 AC: 20788 AN: 53356

Middle Eastern (MID) AF: 0.642 AC: 3693 AN: 5756

European-Non Finnish (NFE) AF: 0.373 AC: 414486 AN: 1111036

Other (OTH) AF: 0.474 AC: 28611 AN: 60348

GnomAD4 genome AF: 0.514 AC: 78206 AN: 152038 Hom.: 21315 Cov.: 32 AF XY: 0.519 AC XY: 38542 AN XY: 74318

African (AFR) AF: 0.665 AC: 27572 AN: 41462

American (AMR) AF: 0.611 AC: 9331 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.594 AC: 2059 AN: 3468

East Asian (EAS) AF: 0.720 AC: 3710 AN: 5154

South Asian (SAS) AF: 0.585 AC: 2820 AN: 4822

European-Finnish (FIN) AF: 0.392 AC: 4148 AN: 10574

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.394 AC: 26784 AN: 67980

Other (OTH) AF: 0.538 AC: 1137 AN: 2114

Alfa AF: 0.444 Hom.: 24615

Bravo AF: 0.538

Asia WGS AF: 0.622 AC: 2164 AN: 3478

EpiCase AF: 0.428

EpiControl AF: 0.426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.3
DANN	Benign	0.72
PhyloP100		-1.2
Mutation Taster		=98/2	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: rs945453; hg19: chr1-216692669; COSMIC: COSV63153449;