rs9322354

Variant names:

• chr6-152060879-A-G
• rs9322354
• NM_000125.4:c.1236-112A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000125.4(ESR1):​c.1236-112A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 857,232 control chromosomes in the GnomAD database, including 14,693 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (5300 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9393 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.129
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-152060879-A-G is Benign according to our data. Variant chr6-152060879-A-G is described in ClinVar as Benign. ClinVar VariationId is 1292722.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1236-112A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1242-112A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1236-112A>G		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1236-112A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-112A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.717-112A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33277 AN: 151964 Hom.: 5290 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.142 AC: 100222 AN: 705150 Hom.: 9393 AF XY: 0.144 AC XY: 52886 AN XY: 366040

African (AFR) AF: 0.444 AC: 7529 AN: 16976

American (AMR) AF: 0.0772 AC: 1869 AN: 24204

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 1938 AN: 18814

East Asian (EAS) AF: 0.333 AC: 10676 AN: 32024

South Asian (SAS) AF: 0.218 AC: 11940 AN: 54848

European-Finnish (FIN) AF: 0.195 AC: 6688 AN: 34368

Middle Eastern (MID) AF: 0.141 AC: 368 AN: 2614

European-Non Finnish (NFE) AF: 0.110 AC: 53645 AN: 486708

Other (OTH) AF: 0.161 AC: 5569 AN: 34594

GnomAD4 genome AF: 0.219 AC: 33324 AN: 152082 Hom.: 5300 Cov.: 32 AF XY: 0.220 AC XY: 16368 AN XY: 74344

African (AFR) AF: 0.436 AC: 18069 AN: 41446

American (AMR) AF: 0.106 AC: 1628 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3468

East Asian (EAS) AF: 0.369 AC: 1913 AN: 5182

South Asian (SAS) AF: 0.230 AC: 1109 AN: 4824

European-Finnish (FIN) AF: 0.200 AC: 2115 AN: 10562

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7520 AN: 67988

Other (OTH) AF: 0.205 AC: 434 AN: 2114

Alfa AF: 0.206 Hom.: 761

Bravo AF: 0.220

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.74
PhyloP100		-0.13
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: rs9322354; hg19: chr6-152382014;