NM_001438.4:c.862+13346T>C

Variant names:

• chr1-216550873-A-G
• rs1846224
• NM_001438.4:c.862+13346T>C

Variant summary

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

The NM_001438.4(ESRRG):​c.862+13346T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,184 control chromosomes in the GnomAD database, including 3,827 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 0.20 (3827 hom., cov: 32)
• Consequence: ESRRG NM_001438.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27
• Publications: 9 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=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRG	NM_001438.4	c.862+13346T>C		intron_variant	Intron 5 of 6	ENST00000408911.8	NP_001429.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRG	ENST00000408911.8	c.862+13346T>C		intron_variant	Intron 5 of 6	1	NM_001438.4	ENSP00000386171.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30315 AN: 152066 Hom.: 3826 Cov.: 32

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.203

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

GnomAD4 genome AF: 0.199 AC: 30319 AN: 152184 Hom.: 3827 Cov.: 32 AF XY: 0.202 AC XY: 15018 AN XY: 74372

African (AFR) AF: 0.0511 AC: 2125 AN: 41546

American (AMR) AF: 0.226 AC: 3453 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 672 AN: 3470

East Asian (EAS) AF: 0.132 AC: 686 AN: 5178

South Asian (SAS) AF: 0.162 AC: 780 AN: 4824

European-Finnish (FIN) AF: 0.313 AC: 3315 AN: 10590

Middle Eastern (MID) AF: 0.171 AC: 50 AN: 292

European-Non Finnish (NFE) AF: 0.271 AC: 18445 AN: 67998

Other (OTH) AF: 0.206 AC: 435 AN: 2112

Alfa AF: 0.242 Hom.: 15276

Bravo AF: 0.188

Asia WGS AF: 0.151 AC: 523 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.015
DANN	Benign	0.52
PhyloP100		-2.3
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: rs1846224; hg19: chr1-216724215;