rs17669622

Variant names:

• chr1-216583479-G-A
• rs17669622
• NM_001438.4:c.590-15381C>T

Variant summary

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

The ENST00000408911.8(ESRRG):​c.590-15381C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,266 control chromosomes in the GnomAD database, including 3,249 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 0.19 (3249 hom., cov: 33)
• Consequence: ESRRG ENST00000408911.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.353
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000408911.8. 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_001438.4	MANE Select	c.590-15381C>T		intron	N/A	NP_001429.2
	ESRRG	NM_001243518.2		c.605-15381C>T		intron	N/A	NP_001230447.1
	ESRRG	NM_001134285.3		c.521-15381C>T		intron	N/A	NP_001127757.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRG	ENST00000408911.8	TSL:1 MANE Select	c.590-15381C>T		intron	N/A	ENSP00000386171.3
	ESRRG	ENST00000366937.5	TSL:1	c.605-15381C>T		intron	N/A	ENSP00000355904.1
	ESRRG	ENST00000359162.6	TSL:1	c.521-15381C>T		intron	N/A	ENSP00000352077.2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28182 AN: 152148 Hom.: 3250 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.214

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.185 AC: 28188 AN: 152266 Hom.: 3249 Cov.: 33 AF XY: 0.182 AC XY: 13570 AN XY: 74446

African (AFR) AF: 0.0483 AC: 2009 AN: 41564

American (AMR) AF: 0.214 AC: 3274 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 968 AN: 3470

East Asian (EAS) AF: 0.182 AC: 943 AN: 5182

South Asian (SAS) AF: 0.181 AC: 872 AN: 4824

European-Finnish (FIN) AF: 0.199 AC: 2110 AN: 10614

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17421 AN: 68012

Other (OTH) AF: 0.208 AC: 439 AN: 2114

Alfa AF: 0.231 Hom.: 6467

Bravo AF: 0.181

Asia WGS AF: 0.159 AC: 550 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.56
DANN	Benign	0.48
PhyloP100		-0.35
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: rs17669622; hg19: chr1-216756821;