rs2185226

Variant names:

• chr1-217002518-A-G
• rs2185226
• ENST00000359162.6:c.-105-62845T>C

Variant summary

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

The ENST00000359162.6(ESRRG):​c.-105-62845T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 151,760 control chromosomes in the GnomAD database, including 12,372 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 0.36 (12372 hom., cov: 30)
• Consequence: ESRRG ENST00000359162.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.109
• Publications: 6 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=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359162.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRG	NM_001134285.3		c.-229-42833T>C		intron	N/A	NP_001127757.1
	ESRRG	NM_001243509.2		c.-577-1794T>C		intron	N/A	NP_001230438.1
	ESRRG	NM_001243510.3		c.-223-62845T>C		intron	N/A	NP_001230439.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRG	ENST00000359162.6	TSL:1	c.-105-62845T>C		intron	N/A	ENSP00000352077.2
	ESRRG	ENST00000366940.6	TSL:1	c.-229-42833T>C		intron	N/A	ENSP00000355907.2
	ESRRG	ENST00000493603.5	TSL:1	c.-223-62845T>C		intron	N/A	ENSP00000419594.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54718 AN: 151640 Hom.: 12346 Cov.: 30

Gnomad AFR AF: 0.628

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.299

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.522

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.329

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

GnomAD4 genome AF: 0.361 AC: 54807 AN: 151760 Hom.: 12372 Cov.: 30 AF XY: 0.361 AC XY: 26771 AN XY: 74174

African (AFR) AF: 0.629 AC: 25996 AN: 41356

American (AMR) AF: 0.299 AC: 4552 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 964 AN: 3466

East Asian (EAS) AF: 0.522 AC: 2673 AN: 5118

South Asian (SAS) AF: 0.407 AC: 1954 AN: 4800

European-Finnish (FIN) AF: 0.205 AC: 2167 AN: 10552

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.230 AC: 15639 AN: 67922

Other (OTH) AF: 0.331 AC: 696 AN: 2100

Alfa AF: 0.261 Hom.: 6730

Bravo AF: 0.379

Asia WGS AF: 0.448 AC: 1558 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.76
PhyloP100		0.11
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: rs2185226; hg19: chr1-217175860;