1-216623420-G-A

Variant names:

• chr1-216623420-G-A
• rs4567343
• NM_001438.4:c.589+27553C>T

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_001438.4(ESRRG):c.589+27553C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000659 (AC=1) in the gnomAD database across 151,830 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000242. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: ESRRG NM_001438.4 intron
• Predictors: AlphaGenome AVI: 0.6: Benign
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469
• Publications: 4 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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000242 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001438.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ESRRG NM_001438.4	MANE Select	c.589+27553C>T	intron	Intron 3 of 6	Prot: NP_001429.2
	ESRRG NM_001243518.2		c.604+27553C>T	intron	Intron 4 of 7	Prot: NP_001230447.1 UniProt:
	ESRRG NM_001134285.3		c.520+27553C>T	intron	Intron 5 of 8	Prot: NP_001127757.1 UniProt:

ESRRG NM_001438.4

MANE Select

HGVSc / HGVSpc.589+27553C>T

Exon rankIntron 3 of 6

intron

Prot: NP_001429.2

ESRRG NM_001243518.2

HGVSc / HGVSpc.604+27553C>T

Exon rankIntron 4 of 7

intron

Prot: NP_001230447.1UniProt: P62508-5

ESRRG NM_001134285.3

HGVSc / HGVSpc.520+27553C>T

Exon rankIntron 5 of 8

intron

Prot: NP_001127757.1UniProt: P62508-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ESRRG ENST00000408911.8	TSL:1MANE Select	c.589+27553C>T	intron	Intron 3 of 6	Prot: ENSP00000386171.3 UniProt:
	ESRRG ENST00000366937.5	TSL:1	c.604+27553C>T	intron	Intron 4 of 7	Prot: ENSP00000355904.1 UniProt:
	ESRRG ENST00000359162.6	TSL:1	c.520+27553C>T	intron	Intron 4 of 7	Prot: ENSP00000352077.2 UniProt:

ESRRG ENST00000408911.8

TSL:1MANE Select

HGVSc / HGVSpc.589+27553C>T

Exon rankIntron 3 of 6

intron

Prot: ENSP00000386171.3UniProt: P62508-1

ESRRG ENST00000366937.5

TSL:1

HGVSc / HGVSpc.604+27553C>T

Exon rankIntron 4 of 7

intron

Prot: ENSP00000355904.1UniProt: P62508-5

ESRRG ENST00000359162.6

TSL:1

HGVSc / HGVSpc.520+27553C>T

Exon rankIntron 4 of 7

intron

Prot: ENSP00000352077.2UniProt: P62508-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000659	AC:1	Hom:0	AN:151830	Cov:31
GnomAD4 genome	AF: 0.00000659	AC:1	Hom:0	AN:151830	Cov:31
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:1539	AN:21682	Cov:

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.59
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.96
DANN	Benign	0.92
GPN-Star LLR	N/A	-0.17
GPN-Star score	N/A	-0.17
PhyloP100	Benign	-0.47

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs4567343;

hg19: chr1-216796762;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar