1-216623420-G-T

Variant names:

• chr1-216623420-G-T
• rs4567343
• NM_001438.4:c.589+27553C>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.589+27553C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,858 control chromosomes in the GnomAD database, including 14,661 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 0.42 (14661 hom., cov: 31)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469

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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.589+27553C>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.589+27553C>A		intron_variant	Intron 3 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64147 AN: 151740 Hom.: 14638 Cov.: 31

Gnomad AFR AF: 0.597

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.392

Gnomad EAS AF: 0.526

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.417

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

GnomAD4 genome AF: 0.423 AC: 64208 AN: 151858 Hom.: 14661 Cov.: 31 AF XY: 0.424 AC XY: 31448 AN XY: 74214

Gnomad4 AFR AF: 0.596 AC: 0.596444 AN: 0.596444

Gnomad4 AMR AF: 0.416 AC: 0.416317 AN: 0.416317

Gnomad4 ASJ AF: 0.392 AC: 0.392219 AN: 0.392219

Gnomad4 EAS AF: 0.527 AC: 0.526612 AN: 0.526612

Gnomad4 SAS AF: 0.384 AC: 0.384248 AN: 0.384248

Gnomad4 FIN AF: 0.368 AC: 0.368261 AN: 0.368261

Gnomad4 NFE AF: 0.325 AC: 0.325211 AN: 0.325211

Gnomad4 OTH AF: 0.415 AC: 0.414692 AN: 0.414692

Alfa AF: 0.292 Hom.: 1014

Bravo AF: 0.437

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.34
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

Publications

LitVar

Other links and lift over

dbSNP: rs4567343; hg19: chr1-216796762; COSMIC: COSV63153734;