6-151807942-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000125.4(ESR1):c.30T>C(p.Ser10=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,166 control chromosomes in the GnomAD database, including 182,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17171 hom., cov: 33)
  • Exomes 𝑓: 0.47 (165449 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.664

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-151807942-T-C is Benign according to our data. Variant chr6-151807942-T-C is described in ClinVar as [Benign]. Clinvar id is 1250979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.664 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.30T>C	p.Ser10=	synonymous_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.30T>C	p.Ser10=	synonymous_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72099 AN: 151918 Hom.: 17166 Cov.: 33

Gnomad AFR AF: 0.489

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.463 AC: 114483 AN: 247438 Hom.: 26590 AF XY: 0.465 AC XY: 62395 AN XY: 134134

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.510

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.493

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.476

Gnomad OTH exome AF: 0.465

GnomAD4 exome AF: 0.475 AC: 693862 AN: 1461130 Hom.: 165449 Cov.: 50 AF XY: 0.475 AC XY: 345476 AN XY: 726860

Gnomad4 AFR exome AF: 0.489

Gnomad4 AMR exome AF: 0.450

Gnomad4 ASJ exome AF: 0.509

Gnomad4 EAS exome AF: 0.390

Gnomad4 SAS exome AF: 0.486

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.479

Gnomad4 OTH exome AF: 0.481

GnomAD4 genome AF: 0.474 AC: 72129 AN: 152036 Hom.: 17171 Cov.: 33 AF XY: 0.472 AC XY: 35058 AN XY: 74300

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.511

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.498

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.480

Gnomad4 OTH AF: 0.464

Alfa AF: 0.469 Hom.: 24155

Bravo AF: 0.472

Asia WGS AF: 0.445 AC: 1548 AN: 3478

EpiCase AF: 0.477

EpiControl AF: 0.476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 17, 2018

- -

Familial cancer of breast;C1832662:Myocardial infarction, susceptibility to;C3809250:Estrogen resistance syndrome;C3887485:Migraine with or without aura, susceptibility to, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	7.2
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs2077647; hg19: chr6-152129077; COSMIC: COSV52785128; COSMIC: COSV52785128;