chr6-151930433-T-C

Variant names:

• chr6-151930433-T-C
• rs2347868
• NM_000125.4:c.761-13740T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):​c.761-13740T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.805 in 152,178 control chromosomes in the GnomAD database, including 50,232 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (50232 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.945 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.761-13740T>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.767-13740T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.761-13740T>C		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.761-13740T>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+122069T>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.242-13740T>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122402 AN: 152060 Hom.: 50187 Cov.: 32

Gnomad AFR AF: 0.953

Gnomad AMI AF: 0.853

Gnomad AMR AF: 0.751

Gnomad ASJ AF: 0.801

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.724

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.804

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.805 AC: 122503 AN: 152178 Hom.: 50232 Cov.: 32 AF XY: 0.796 AC XY: 59197 AN XY: 74358

African (AFR) AF: 0.953 AC: 39592 AN: 41552

American (AMR) AF: 0.751 AC: 11476 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 2781 AN: 3470

East Asian (EAS) AF: 0.499 AC: 2581 AN: 5168

South Asian (SAS) AF: 0.591 AC: 2855 AN: 4828

European-Finnish (FIN) AF: 0.724 AC: 7647 AN: 10560

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52871 AN: 68002

Other (OTH) AF: 0.799 AC: 1688 AN: 2112

Alfa AF: 0.778 Hom.: 39429

Bravo AF: 0.814

Asia WGS AF: 0.587 AC: 2043 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.78
DANN	Benign	0.58
PhyloP100		-1.2
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: rs2347868; hg19: chr6-152251568;