6-151808321-A-G

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.409A>G(p.Ser137Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,554,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.508

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=0.0073446035).
• BP6: Variant 6-151808321-A-G is Benign according to our data. Variant chr6-151808321-A-G is described in ClinVar as [Benign]. Clinvar id is 735137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-151808321-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.409A>G	p.Ser137Gly	missense_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.409A>G	p.Ser137Gly	missense_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 418 AN: 151010 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000148

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000487 AC: 85 AN: 174604 Hom.: 0 AF XY: 0.000323 AC XY: 31 AN XY: 95914

Gnomad AFR exome AF: 0.00710

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 338 AN: 1402980 Hom.: 0 Cov.: 36 AF XY: 0.000202 AC XY: 140 AN XY: 692380

Gnomad4 AFR exome AF: 0.00913

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000369

Gnomad4 OTH exome AF: 0.000468

GnomAD4 genome AF: 0.00279 AC: 421 AN: 151102 Hom.: 3 Cov.: 32 AF XY: 0.00256 AC XY: 189 AN XY: 73848

Gnomad4 AFR AF: 0.00970

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.0000241 Hom.: 0

Bravo AF: 0.00321

ESP6500AA AF: 0.00407 AC: 17

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000446 AC: 52

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

Invitae

Dec 31, 2019

- -

ESR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as 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	0.053
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.33	T;T;T;T;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.33	N
MetaRNN	Benign	0.0073	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N;N;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N
REVEL	Benign	0.013
Sift	Benign	0.21	T;T;T;T;D;T
Sift4G	Benign	0.30	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;.
Vest4		0.057
MVP		0.44
MPC		0.47
ClinPred		0.041	T
GERP RS		1.2
Varity_R		0.097
gMVP		0.26

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: rs185717042; hg19: chr6-152129456;