1-216542978-G-T

Variant names:

• chr1-216542978-G-T
• rs12145418
• NM_001438.4:c.862+21241C>A

Variant summary

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

The NM_001438.4(ESRRG):​c.862+21241C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 151,900 control chromosomes in the GnomAD database, including 7,376 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 0.29 (7376 hom., cov: 33)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.686
• Publications: 9 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 (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.862+21241C>A		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.862+21241C>A		intron_variant	Intron 5 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43580 AN: 151782 Hom.: 7366 Cov.: 33

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.330

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.296

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

GnomAD4 genome AF: 0.287 AC: 43601 AN: 151900 Hom.: 7376 Cov.: 33 AF XY: 0.293 AC XY: 21747 AN XY: 74220

African (AFR) AF: 0.108 AC: 4493 AN: 41468

American (AMR) AF: 0.396 AC: 6020 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 961 AN: 3464

East Asian (EAS) AF: 0.330 AC: 1700 AN: 5148

South Asian (SAS) AF: 0.285 AC: 1373 AN: 4820

European-Finnish (FIN) AF: 0.395 AC: 4181 AN: 10574

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23760 AN: 67894

Other (OTH) AF: 0.298 AC: 631 AN: 2114

Alfa AF: 0.322 Hom.: 9779

Bravo AF: 0.282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.2
DANN	Benign	0.30
PhyloP100		0.69
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: rs12145418; hg19: chr1-216716320;