rs3862955

Variant names:

• chr1-216522130-T-C
• rs3862955
• NM_001438.4:c.863-2709A>G

Variant summary

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

The NM_001438.4(ESRRG):​c.863-2709A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0831 in 151,992 control chromosomes in the GnomAD database, including 666 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 0.083 (666 hom., cov: 31)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.11
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.863-2709A>G		intron_variant	Intron 5 of 6	ENST00000408911.8	NP_001429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000408911.8	c.863-2709A>G		intron_variant	Intron 5 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.0831 AC: 12615 AN: 151874 Hom.: 659 Cov.: 31

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0669

Gnomad OTH AF: 0.0813

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0831 AC: 12634 AN: 151992 Hom.: 666 Cov.: 31 AF XY: 0.0872 AC XY: 6480 AN XY: 74316

African (AFR) AF: 0.0614 AC: 2545 AN: 41482

American (AMR) AF: 0.173 AC: 2632 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 287 AN: 3470

East Asian (EAS) AF: 0.164 AC: 845 AN: 5140

South Asian (SAS) AF: 0.115 AC: 552 AN: 4820

European-Finnish (FIN) AF: 0.0835 AC: 883 AN: 10578

Middle Eastern (MID) AF: 0.103 AC: 30 AN: 292

European-Non Finnish (NFE) AF: 0.0669 AC: 4545 AN: 67962

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0827 Hom.: 107

Bravo AF: 0.0894

Asia WGS AF: 0.136 AC: 472 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.4
DANN	Benign	0.79
PhyloP100		1.1
Mutation Taster		=100/0	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: rs3862955; hg19: chr1-216695472;