6-151807507-A-G

Position:

• chr6-151807507-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001122740.2(ESR1):​c.-73A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 299,578 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (258 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (37 hom.)
• Consequence: ESR1 NM_001122740.2 splice_region
• Scores: Splicing: ADA: 0.0003525
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 6-151807507-A-G is Benign according to our data. Variant chr6-151807507-A-G is described in ClinVar as [Benign]. Clinvar id is 1268885.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_001122740.2	c.-73A>G		splice_region_variant	1/9		NP_001116212.1
ESR1	XM_047418292.1	c.-73A>G		splice_region_variant	1/8		XP_047274248.1
ESR1	XM_047418296.1	c.-73A>G		splice_region_variant	1/8		XP_047274252.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000446550.1	c.-73A>G		splice_region_variant	1/2	1		ENSP00000411105.1
ESR1	ENST00000446550.1	c.-73A>G		5_prime_UTR_variant	1/2	1		ENSP00000411105.1
ESR1	ENST00000404742.5	c.-70-336A>G		intron_variant		1		ENSP00000385373.1

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5022 AN: 152112 Hom.: 257 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.00732 AC: 1078 AN: 147348 Hom.: 37 Cov.: 0 AF XY: 0.00743 AC XY: 570 AN XY: 76692

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.00940

Gnomad4 ASJ exome AF: 0.000245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000747

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.0331 AC: 5033 AN: 152230 Hom.: 258 Cov.: 31 AF XY: 0.0319 AC XY: 2378 AN XY: 74434

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0261 Hom.: 63

Bravo AF: 0.0383

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.0040
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: rs867240; hg19: chr6-152128642;