6-151808027-C-G

Variant names:

• chr6-151808027-C-G
• rs781772511
• NM_000125.4:c.115C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000125.4(ESR1):​c.115C>G​(p.Leu39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L39L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.36
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a mutagenesis_site Impairs AF-1 transactivation. (size 0) in uniprot entity ESR1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38713372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.115C>G	p.Leu39Val	missense_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.115C>G	p.Leu39Val	missense_variant	Exon 1 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T;T;T;T;T;T;T;T
Eigen	Benign	0.092
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.90	.;L;L;.;L;L;.;.
PhyloP100		2.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;N;N;N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D;D;D;D;D;D;D;D
Sift4G	Benign	0.091	T;T;T;D;T;T;D;D
Polyphen		0.44, 0.89	.;B;B;.;B;B;P;.
Vest4		0.38, 0.38, 0.32, 0.28, 0.29, 0.45
MutPred		0.61		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.90
MPC		0.67
ClinPred		0.67	D
GERP RS		2.3
PromoterAI		-0.0056	Neutral
Varity_R		0.18
gMVP		0.55
Mutation Taster		=75/25	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: rs781772511; hg19: chr6-152129162;