6-151807928-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000125.4(ESR1):c.16C>T(p.His6Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0045 in 1,613,882 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H6H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (23 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.94

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012596518).
• BP6: Variant 6-151807928-C-T is Benign according to our data. Variant chr6-151807928-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 712708.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.16C>T	p.His6Tyr	missense_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.16C>T	p.His6Tyr	missense_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.00309 AC: 470 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00519

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00327 AC: 811 AN: 248082 Hom.: 2 AF XY: 0.00323 AC XY: 435 AN XY: 134520

Gnomad AFR exome AF: 0.000746

Gnomad AMR exome AF: 0.000898

Gnomad ASJ exome AF: 0.00428

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00431

Gnomad NFE exome AF: 0.00515

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00465 AC: 6791 AN: 1461566 Hom.: 23 Cov.: 30 AF XY: 0.00449 AC XY: 3266 AN XY: 727092

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.00443

Gnomad4 NFE exome AF: 0.00534

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00273 AC XY: 203 AN XY: 74468

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00517

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00431 Hom.: 1

Bravo AF: 0.00273

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00512 AC: 44

ExAC AF: 0.00348 AC: 422

EpiCase AF: 0.00529

EpiControl AF: 0.00534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ESR1: PP3, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2019	Identified in an individual with primary ovarian insufficiency, however, functional studies in HEK293T cells demonstrated that the variant showed similar transcriptional activity to wild type (Bouilly et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23074960, 27603904) -

ESR1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;T;T;T;T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.97	D;.;.;D;D;.;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.013	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.0	D;N;N;D;N;N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D;D;D;T;D;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;D;T;T;D;D
Polyphen		0.99, 1.0	.;D;D;.;D;D;D;.
Vest4		0.56, 0.56, 0.55, 0.52, 0.30, 0.40
MVP		0.80
MPC		1.3
ClinPred		0.047	T
GERP RS		5.2
Varity_R		0.16
gMVP		0.74

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: rs139960913; hg19: chr6-152129063; COSMIC: COSV52793297; COSMIC: COSV52793297;