6-151808264-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000125.4(ESR1):c.352T>C(p.Ser118Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00449 in 1,584,834 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (25 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.36

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009224892).
• BP6: Variant 6-151808264-T-C is Benign according to our data. Variant chr6-151808264-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 790988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.352T>C	p.Ser118Pro	missense_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.352T>C	p.Ser118Pro	missense_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.00416 AC: 633 AN: 152122 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00482

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00439 AC: 867 AN: 197410 Hom.: 7 AF XY: 0.00421 AC XY: 455 AN XY: 108014

Gnomad AFR exome AF: 0.000730

Gnomad AMR exome AF: 0.00353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000546

Gnomad FIN exome AF: 0.0167

Gnomad NFE exome AF: 0.00506

Gnomad OTH exome AF: 0.00596

GnomAD4 exome AF: 0.00452 AC: 6475 AN: 1432594 Hom.: 25 Cov.: 36 AF XY: 0.00437 AC XY: 3103 AN XY: 709262

Gnomad4 AFR exome AF: 0.000454

Gnomad4 AMR exome AF: 0.00383

Gnomad4 ASJ exome AF: 0.0000792

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000438

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00476

Gnomad4 OTH exome AF: 0.00380

GnomAD4 genome AF: 0.00416 AC: 633 AN: 152240 Hom.: 2 Cov.: 32 AF XY: 0.00470 AC XY: 350 AN XY: 74434

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00482

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00391 Hom.: 0

Bravo AF: 0.00311

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000970 AC: 4

ESP6500EA AF: 0.00331 AC: 27

ExAC AF: 0.00372 AC: 444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ESR1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T;T;T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.68	D
MetaRNN	Benign	0.0092	T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Uncertain	2.7	M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;D;D;D;N;D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.039	D;D;D;D;D;D
Polyphen		0.039	B;B;B;B;D;.
Vest4		0.37
MVP		0.64
MPC		1.5
ClinPred		0.035	T
GERP RS		4.9
Varity_R		0.72
gMVP		0.73

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: rs200075329; hg19: chr6-152129399;