1-216985701-A-G

Variant names:

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

Variant summary

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

The ENST00000359162.6(ESRRG):​c.-105-46028T>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 ENST00000359162.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.916
• Publications: 2 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=-0.97).
• 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.833 AC: 10 AN: 12

Other (OTH) AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.890 AC: 36941 AN: 41506

American (AMR) AF: 0.867 AC: 13262 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.823 AC: 2857 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5157 AN: 5162

South Asian (SAS) AF: 0.843 AC: 4063 AN: 4822

European-Finnish (FIN) AF: 0.882 AC: 9342 AN: 10590

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.819 AC: 55657 AN: 67996

Other (OTH) AF: 0.828 AC: 1744 AN: 2106

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
PhyloP100		-0.92
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: rs946437; hg19: chr1-217159043;