6-151807743-C-T

Variant names:

• chr6-151807743-C-T
• rs9340772
• NM_000125.4:c.-170C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000125.4(ESR1):​c.-170C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 713,154 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0094 (24 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (9 hom.)
• Consequence: ESR1 NM_000125.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.562
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 6-151807743-C-T is Benign according to our data. Variant chr6-151807743-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1185886.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00945 (1439/152344) while in subpopulation AFR AF = 0.033 (1372/41582). AF 95% confidence interval is 0.0315. There are 24 homozygotes in GnomAd4. There are 669 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.-170C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	ENST00000206249.8	NP_000116.2
ESR1	NM_000125.4	c.-170C>T		5_prime_UTR_variant	Exon 1 of 8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.-170C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3
ESR1	ENST00000206249.8	c.-170C>T		5_prime_UTR_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.00942 AC: 1434 AN: 152226 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00131 AC: 737 AN: 560810 Hom.: 9 Cov.: 6 AF XY: 0.00102 AC XY: 302 AN XY: 297030

African (AFR) AF: 0.0342 AC: 542 AN: 15866

American (AMR) AF: 0.00222 AC: 71 AN: 32012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17540

East Asian (EAS) AF: 0.00 AC: 0 AN: 31932

South Asian (SAS) AF: 0.0000177 AC: 1 AN: 56344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31720

Middle Eastern (MID) AF: 0.00123 AC: 3 AN: 2442

European-Non Finnish (NFE) AF: 0.0000555 AC: 19 AN: 342638

Other (OTH) AF: 0.00333 AC: 101 AN: 30316

GnomAD4 genome AF: 0.00945 AC: 1439 AN: 152344 Hom.: 24 Cov.: 31 AF XY: 0.00898 AC XY: 669 AN XY: 74490

African (AFR) AF: 0.0330 AC: 1372 AN: 41582

American (AMR) AF: 0.00281 AC: 43 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68028

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.0108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 22, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.0
DANN	Benign	0.89
PhyloP100		-0.56
PromoterAI		-0.037	Neutral
Mutation Taster		=300/0	polymorphism

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: rs9340772; hg19: chr6-152128878;