1-216885137-C-T

Position:

• chr1-216885137-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000359162.6(ESRRG):​c.-14+54445G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 151,812 control chromosomes in the GnomAD database, including 29,662 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 0.62 (29662 hom., cov: 31)
• Consequence: ESRRG ENST00000359162.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.747

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRRG	NM_001134285.3	c.-14+54445G>A		intron_variant			NP_001127757.1
ESRRG	NM_001243505.2	c.-282-19959G>A		intron_variant			NP_001230434.1
ESRRG	NM_001243506.2	c.-84+54445G>A		intron_variant			NP_001230435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000359162.6	c.-14+54445G>A		intron_variant		1		ENSP00000352077
ESRRG	ENST00000361395.6	c.-131-19959G>A		intron_variant		1		ENSP00000354584
ESRRG	ENST00000366938.6	c.-190+54445G>A		intron_variant		1		ENSP00000355905

Frequencies

GnomAD3 genomes AF: 0.619 AC: 93861 AN: 151694 Hom.: 29654 Cov.: 31

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.804

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.597

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

GnomAD4 genome AF: 0.619 AC: 93913 AN: 151812 Hom.: 29662 Cov.: 31 AF XY: 0.618 AC XY: 45840 AN XY: 74170

Gnomad4 AFR AF: 0.688

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.658

Gnomad4 NFE AF: 0.606

Gnomad4 OTH AF: 0.591

Alfa AF: 0.602 Hom.: 60469

Bravo AF: 0.617

Asia WGS AF: 0.377 AC: 1314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs1436900; hg19: chr1-217058479;