Genetic Variant NM_001438.4:c.472+9C>T (chr1-216677067-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001438.4(ESRRG):c.472+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,608,536 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 38 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 35 hom. )

Consequence

ESRRG
NM_001438.4 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.416

Publications

2 publications found

Variant links:

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]

ESRRG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 1-216677067-G-A is Benign according to our data. Variant chr1-216677067-G-A is described in ClinVar as Benign. ClinVar VariationId is 775167.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0124 (1891/152214) while in subpopulation AFR AF = 0.0432 (1792/41526). AF 95% confidence interval is 0.0415. There are 38 homozygotes in GnomAd4. There are 904 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1891 AD gene.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESRRG	NM_001438.4	MANE Select	c.472+9C>T	intron	N/A	NP_001429.2
ESRRG	NM_001243518.2		c.487+9C>T	intron	N/A	NP_001230447.1	P62508-5
ESRRG	NM_001134285.3		c.403+9C>T	intron	N/A	NP_001127757.1	P62508-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESRRG	ENST00000408911.8	TSL:1 MANE Select	c.472+9C>T	intron	N/A	ENSP00000386171.3	P62508-1
ESRRG	ENST00000366937.5	TSL:1	c.487+9C>T	intron	N/A	ENSP00000355904.1	P62508-5
ESRRG	ENST00000359162.6	TSL:1	c.403+9C>T	intron	N/A	ENSP00000352077.2	P62508-2

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1887

AN:

152096

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0432

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00328

AC:

817

AN:

248902

AF XY:

0.00226

show subpopulations

Gnomad AFR exome

AF:

0.0428

Gnomad AMR exome

AF:

0.00223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000467

Gnomad NFE exome

AF:

0.000250

Gnomad OTH exome

AF:

0.00197

GnomAD4 exome

AF:

0.00139

AC:

2029

AN:

1456322

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

863

AN XY:

724006

show subpopulations

African (AFR)

AF:

0.0440

AC:

1468

AN:

33396

American (AMR)

AF:

0.00249

AC:

111

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25848

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.000105

AC:

AN:

85928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00436

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.000190

AC:

210

AN:

1107674

Other (OTH)

AF:

0.00342

AC:

206

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

100

201

301

402

502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0124

AC:

1891

AN:

152214

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

904

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0432

AC:

1792

AN:

41526

American (AMR)

AF:

0.00477

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68012

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

190

286

381

476

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00689

Hom.:

Bravo

AF:

0.0141

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

-0.42

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over