NM_001438.4:c.590-22500G>A

Variant names:

• chr1-216590598-C-T
• rs7519402
• NM_001438.4:c.590-22500G>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.590-22500G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,008 control chromosomes in the GnomAD database, including 18,320 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 0.47 (18320 hom., cov: 33)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.463
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.590-22500G>A		intron_variant	Intron 3 of 6	ENST00000408911.8	NP_001429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000408911.8	c.590-22500G>A		intron_variant	Intron 3 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70644 AN: 151890 Hom.: 18261 Cov.: 33

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.421

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.442

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

GnomAD4 genome AF: 0.465 AC: 70758 AN: 152008 Hom.: 18320 Cov.: 33 AF XY: 0.463 AC XY: 34383 AN XY: 74276

African (AFR) AF: 0.706 AC: 29271 AN: 41464

American (AMR) AF: 0.429 AC: 6560 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1473 AN: 3468

East Asian (EAS) AF: 0.477 AC: 2458 AN: 5158

South Asian (SAS) AF: 0.421 AC: 2032 AN: 4822

European-Finnish (FIN) AF: 0.360 AC: 3791 AN: 10544

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23867 AN: 67958

Other (OTH) AF: 0.440 AC: 931 AN: 2114

Alfa AF: 0.414 Hom.: 1786

Bravo AF: 0.482

Asia WGS AF: 0.438 AC: 1518 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.32
DANN	Benign	0.72
PhyloP100		-0.46
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: rs7519402; hg19: chr1-216763940;