1-216985701-A-G

Variant names:

• chr1-216985701-A-G
• rs946437
• ENST00000359162.6:c.-105-46028T>C

Variant summary

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

The NM_206594.3(ESRRG):​c.-223-46028T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 152,162 control chromosomes in the GnomAD database, including 55,744 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 0.85 (55739 hom., cov: 31)
  • Exomes 𝑓: 0.86 (5 hom.)
• Consequence: ESRRG NM_206594.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.916

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001134285.3	c.-229-26016T>C		intron_variant	Intron 1 of 8		NP_001127757.1
ESRRG	NM_001243509.2	c.-106+14552T>C		intron_variant	Intron 2 of 8		NP_001230438.1
ESRRG	NM_001243510.3	c.-223-46028T>C		intron_variant	Intron 1 of 8		NP_001230439.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000359162.6	c.-105-46028T>C		intron_variant	Intron 1 of 7	1		ENSP00000352077.2
ESRRG	ENST00000366940.6	c.-229-26016T>C		intron_variant	Intron 1 of 8	1		ENSP00000355907.2
ESRRG	ENST00000493603.5	c.-223-46028T>C		intron_variant	Intron 1 of 8	1		ENSP00000419594.1

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129912 AN: 152030 Hom.: 55686 Cov.: 31

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.859

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.823

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.882

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.819

Gnomad OTH AF: 0.825

GnomAD4 exome AF: 0.857 AC: 12 AN: 14 Hom.: 5 AF XY: 0.833 AC XY: 10 AN XY: 12

Gnomad4 AFR exome AF: 1.00

Gnomad4 NFE exome AF: 0.833

GnomAD4 genome AF: 0.855 AC: 130026 AN: 152148 Hom.: 55739 Cov.: 31 AF XY: 0.859 AC XY: 63899 AN XY: 74384

Gnomad4 AFR AF: 0.890

Gnomad4 AMR AF: 0.867

Gnomad4 ASJ AF: 0.823

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.882

Gnomad4 NFE AF: 0.819

Gnomad4 OTH AF: 0.828

Alfa AF: 0.836 Hom.: 6602

Bravo AF: 0.857

Asia WGS AF: 0.926 AC: 3215 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.37
DANN	Benign	0.62

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: rs946437; hg19: chr1-217159043;