6-152101200-C-T

Variant names:

• chr6-152101200-C-T
• rs2747648
• NM_000125.4:c.*2234C>T

Variant summary

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

The NM_000125.4(ESR1):​c.*2234C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.972 in 232,286 control chromosomes in the GnomAD database, including 109,830 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 0.97 (72364 hom., cov: 31)
  • Exomes 𝑓: 0.97 (37466 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.279
• Publications: 30 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 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.*2234C>T		3_prime_UTR	Exon 8 of 8	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.*2234C>T		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*2234C>T		3_prime_UTR	Exon 9 of 9	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.*2234C>T		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3	P03372-1
	ESR1	ENST00000427531.6	TSL:1	c.851-24066C>T		intron	N/A	ENSP00000394721.2	P03372-4
	ESR1	ENST00000440973.5	TSL:5	c.*2234C>T		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1	P03372-1

Frequencies

GnomAD3 genomes AF: 0.975 AC: 148304 AN: 152124 Hom.: 72304 Cov.: 31

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.944

Gnomad AMR AF: 0.967

Gnomad ASJ AF: 0.928

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.988

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.937

Gnomad NFE AF: 0.964

Gnomad OTH AF: 0.962

GnomAD4 exome AF: 0.967 AC: 77430 AN: 80044 Hom.: 37466 Cov.: 0 AF XY: 0.967 AC XY: 35657 AN XY: 36880

African (AFR) AF: 0.994 AC: 3827 AN: 3850

American (AMR) AF: 0.970 AC: 2390 AN: 2464

Ashkenazi Jewish (ASJ) AF: 0.927 AC: 4692 AN: 5060

East Asian (EAS) AF: 1.00 AC: 11110 AN: 11110

South Asian (SAS) AF: 0.986 AC: 682 AN: 692

European-Finnish (FIN) AF: 0.975 AC: 472 AN: 484

Middle Eastern (MID) AF: 0.932 AC: 449 AN: 482

European-Non Finnish (NFE) AF: 0.962 AC: 47382 AN: 49244

Other (OTH) AF: 0.965 AC: 6426 AN: 6658

GnomAD4 genome AF: 0.975 AC: 148423 AN: 152242 Hom.: 72364 Cov.: 31 AF XY: 0.976 AC XY: 72658 AN XY: 74434

African (AFR) AF: 0.994 AC: 41282 AN: 41542

American (AMR) AF: 0.967 AC: 14800 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.928 AC: 3222 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5173 AN: 5176

South Asian (SAS) AF: 0.988 AC: 4765 AN: 4824

European-Finnish (FIN) AF: 0.983 AC: 10403 AN: 10584

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.964 AC: 65608 AN: 68026

Other (OTH) AF: 0.963 AC: 2033 AN: 2112

Alfa AF: 0.968 Hom.: 162427

Bravo AF: 0.974

Asia WGS AF: 0.994 AC: 3450 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.2
DANN	Benign	0.76
PhyloP100		0.28
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: rs2747648; hg19: chr6-152422335;