rs6930355

Variant names:

• chr6-152050256-T-C
• rs6930355
• NM_000125.4:c.1236-10735T>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.1236-10735T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,138 control chromosomes in the GnomAD database, including 5,371 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 0.22 (5371 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.41
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.435 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.1236-10735T>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1242-10735T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1236-10735T>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.1236-10735T>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-10735T>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.717-10735T>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33492 AN: 152020 Hom.: 5365 Cov.: 32

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.220 AC: 33533 AN: 152138 Hom.: 5371 Cov.: 32 AF XY: 0.221 AC XY: 16468 AN XY: 74366

African (AFR) AF: 0.441 AC: 18277 AN: 41484

American (AMR) AF: 0.107 AC: 1634 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3470

East Asian (EAS) AF: 0.369 AC: 1898 AN: 5144

South Asian (SAS) AF: 0.229 AC: 1105 AN: 4824

European-Finnish (FIN) AF: 0.200 AC: 2122 AN: 10596

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

European-Non Finnish (NFE) AF: 0.111 AC: 7520 AN: 68016

Other (OTH) AF: 0.209 AC: 441 AN: 2112

Alfa AF: 0.167 Hom.: 551

Bravo AF: 0.222

Asia WGS AF: 0.294 AC: 1019 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.64
PhyloP100		1.4
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: rs6930355; hg19: chr6-152371391;