rs9341068

Variant names:

• chr6-152098852-A-G
• rs9341068
• NM_000125.4:c.1674A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-152098852-A-G
• chr6-152098852-A-C
• chr6-152098852-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000125.4(ESR1):​c.1674A>G​(p.Ala558Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,184 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (8 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.43
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 6-152098852-A-G is Benign according to our data. Variant chr6-152098852-A-G is described in ClinVar as Benign. ClinVar VariationId is 787838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00574 (874/152292) while in subpopulation AFR AF = 0.02 (833/41558). AF 95% confidence interval is 0.0189. There are 9 homozygotes in GnomAd4. There are 422 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1674A>G	p.Ala558Ala	synonymous	Exon 8 of 8	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1680A>G	p.Ala560Ala	synonymous	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.1674A>G	p.Ala558Ala	synonymous	Exon 9 of 9	NP_001116212.1	P03372-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1674A>G	p.Ala558Ala	synonymous	Exon 8 of 8	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.891A>G	p.Ala297Ala	synonymous	Exon 4 of 4	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000456483.3	TSL:1	c.*549A>G		3_prime_UTR	Exon 5 of 5	ENSP00000415934.3	Q9H2M2

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 862 AN: 152174 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

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: 0.0000441

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00178 AC: 447 AN: 251354 AF XY: 0.00128

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000620 AC: 907 AN: 1461892 Hom.: 8 Cov.: 31 AF XY: 0.000532 AC XY: 387 AN XY: 727248

African (AFR) AF: 0.0212 AC: 711 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1112010

Other (OTH) AF: 0.00152 AC: 92 AN: 60396

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152292 Hom.: 9 Cov.: 32 AF XY: 0.00567 AC XY: 422 AN XY: 74468

African (AFR) AF: 0.0200 AC: 833 AN: 41558

American (AMR) AF: 0.00176 AC: 27 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68024

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00608 Hom.: 6

Bravo AF: 0.00658

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.46
DANN	Benign	0.33
PhyloP100		-1.4
Mutation Taster		=100/0	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: rs9341068; hg19: chr6-152419987;