NM_000125.4:c.1097-95A>G

Variant names:

• chr6-152011561-A-G
• rs9340973
• NM_000125.4:c.1097-95A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000125.4(ESR1):​c.1097-95A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000895 in 1,417,048 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 31)
  • Exomes 𝑓: 0.00045 (6 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.115
• Publications: 0 publications found

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ESR1 Gene-Disease associations (from GenCC):

• estrogen resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 6-152011561-A-G is Benign according to our data. Variant chr6-152011561-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1254013.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-95A>G		intron_variant	Intron 4 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1097-95A>G		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152198 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000449 AC: 568 AN: 1264732 Hom.: 6 AF XY: 0.000372 AC XY: 238 AN XY: 639650

African (AFR) AF: 0.0161 AC: 473 AN: 29456

American (AMR) AF: 0.000790 AC: 35 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24812

East Asian (EAS) AF: 0.00 AC: 0 AN: 38640

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51850

Middle Eastern (MID) AF: 0.000205 AC: 1 AN: 4882

European-Non Finnish (NFE) AF: 0.0000107 AC: 10 AN: 935444

Other (OTH) AF: 0.000894 AC: 48 AN: 53670

GnomAD4 genome AF: 0.00460 AC: 700 AN: 152316 Hom.: 5 Cov.: 31 AF XY: 0.00450 AC XY: 335 AN XY: 74468

African (AFR) AF: 0.0157 AC: 653 AN: 41580

American (AMR) AF: 0.00235 AC: 36 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00298 Hom.: 0

Bravo AF: 0.00527

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 22, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.7
DANN	Benign	0.52
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism

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: rs9340973; hg19: chr6-152332696;