rs9341016

Variant names:

• chr6-152060863-T-C
• rs9341016
• NM_000125.4:c.1236-128T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152060863-T-C
• chr6-152060863-T-A

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.1236-128T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 727,124 control chromosomes in the GnomAD database, including 2,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (295 hom., cov: 32)
  • Exomes 𝑓: 0.068 (1824 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208
• Publications: 9 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-152060863-T-C is Benign according to our data. Variant chr6-152060863-T-C is described in ClinVar as Benign. ClinVar VariationId is 1287180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.151 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1236-128T>C		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1242-128T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1236-128T>C		intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1236-128T>C		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.453-128T>C		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.717-128T>C		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7508 AN: 152226 Hom.: 294 Cov.: 32

Gnomad AFR AF: 0.00989

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0223

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.121

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0593

Gnomad OTH AF: 0.0334

GnomAD4 exome AF: 0.0683 AC: 39283 AN: 574778 Hom.: 1824 AF XY: 0.0720 AC XY: 21816 AN XY: 303190

African (AFR) AF: 0.00988 AC: 144 AN: 14568

American (AMR) AF: 0.0236 AC: 549 AN: 23302

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 690 AN: 17392

East Asian (EAS) AF: 0.114 AC: 3595 AN: 31446

South Asian (SAS) AF: 0.155 AC: 7742 AN: 50014

European-Finnish (FIN) AF: 0.0938 AC: 3016 AN: 32160

Middle Eastern (MID) AF: 0.0530 AC: 122 AN: 2302

European-Non Finnish (NFE) AF: 0.0577 AC: 21531 AN: 373218

Other (OTH) AF: 0.0624 AC: 1894 AN: 30376

GnomAD4 genome AF: 0.0493 AC: 7514 AN: 152346 Hom.: 295 Cov.: 32 AF XY: 0.0527 AC XY: 3928 AN XY: 74494

African (AFR) AF: 0.00988 AC: 411 AN: 41590

American (AMR) AF: 0.0223 AC: 341 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3472

East Asian (EAS) AF: 0.120 AC: 625 AN: 5192

South Asian (SAS) AF: 0.161 AC: 775 AN: 4826

European-Finnish (FIN) AF: 0.0998 AC: 1059 AN: 10614

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0593 AC: 4036 AN: 68022

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0536 Hom.: 31

Bravo AF: 0.0404

Asia WGS AF: 0.135 AC: 470 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.4
DANN	Benign	0.62
PhyloP100		0.21
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: rs9341016; hg19: chr6-152381998;