chr1-216538883-T-A

Variant names:

• chr1-216538883-T-A
• rs1846223
• NM_001438.4:c.863-19462A>T

Variant summary

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

The NM_001438.4(ESRRG):​c.863-19462A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 151,838 control chromosomes in the GnomAD database, including 26,906 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 0.58 (26906 hom., cov: 32)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00300
• Publications: 1 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.788 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.863-19462A>T		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.863-19462A>T		intron_variant	Intron 5 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87470 AN: 151720 Hom.: 26851 Cov.: 32

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.544

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.570

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.548

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

GnomAD4 genome AF: 0.577 AC: 87581 AN: 151838 Hom.: 26906 Cov.: 32 AF XY: 0.576 AC XY: 42703 AN XY: 74172

African (AFR) AF: 0.795 AC: 32938 AN: 41440

American (AMR) AF: 0.565 AC: 8597 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1601 AN: 3460

East Asian (EAS) AF: 0.345 AC: 1768 AN: 5130

South Asian (SAS) AF: 0.347 AC: 1674 AN: 4826

European-Finnish (FIN) AF: 0.570 AC: 6015 AN: 10548

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33193 AN: 67898

Other (OTH) AF: 0.547 AC: 1156 AN: 2112

Alfa AF: 0.548 Hom.: 2923

Bravo AF: 0.589

Asia WGS AF: 0.410 AC: 1424 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		0.0030
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: rs1846223; hg19: chr1-216712225; COSMIC: COSV63153593;