chr6-151963686-T-C

Variant names:

• chr6-151963686-T-C
• rs6557177
• NM_000125.4:c.1096+19178T>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.1096+19178T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 152,220 control chromosomes in the GnomAD database, including 3,320 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 0.20 (3320 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0440
• 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 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.1096+19178T>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1102+19178T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+19178T>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.1096+19178T>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-97305T>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.577+19178T>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30074 AN: 152102 Hom.: 3319 Cov.: 33

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0766

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.204

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

GnomAD4 genome AF: 0.198 AC: 30095 AN: 152220 Hom.: 3320 Cov.: 33 AF XY: 0.190 AC XY: 14172 AN XY: 74448

African (AFR) AF: 0.290 AC: 12029 AN: 41492

American (AMR) AF: 0.135 AC: 2059 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3466

East Asian (EAS) AF: 0.146 AC: 757 AN: 5186

South Asian (SAS) AF: 0.156 AC: 754 AN: 4826

European-Finnish (FIN) AF: 0.0766 AC: 813 AN: 10614

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12426 AN: 68012

Other (OTH) AF: 0.203 AC: 430 AN: 2116

Alfa AF: 0.0855 Hom.: 111

Bravo AF: 0.208

Asia WGS AF: 0.147 AC: 510 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.5
DANN	Benign	0.77
PhyloP100		0.044
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: rs6557177; hg19: chr6-152284821;