11-76516138-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001300942.2(EMSY):c.1559-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 1,605,772 control chromosomes in the GnomAD database, including 312,285 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 0.58 (26440 hom., cov: 31)
  • Exomes 𝑓: 0.62 (285845 hom.)
• Consequence: EMSY NM_001300942.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001893
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.329

Genes affected

EMSY (HGNC:18071): (EMSY transcriptional repressor, BRCA2 interacting) Predicted to enable identical protein binding activity. Predicted to be involved in DNA repair; chromatin organization; and regulation of transcription, DNA-templated. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 11-76516138-G-A is Benign according to our data. Variant chr11-76516138-G-A is described in ClinVar as [Benign]. Clinvar id is 3058884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EMSY	NM_001300942.2	c.1559-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000695367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMSY	ENST00000695367.1	c.1559-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001300942.2

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87968 AN: 151782 Hom.: 26411 Cov.: 31

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.574

GnomAD3 exomes AF: 0.650 AC: 159672 AN: 245470 Hom.: 53500 AF XY: 0.653 AC XY: 86538 AN XY: 132614

Gnomad AFR exome AF: 0.422

Gnomad AMR exome AF: 0.781

Gnomad ASJ exome AF: 0.534

Gnomad EAS exome AF: 0.825

Gnomad SAS exome AF: 0.723

Gnomad FIN exome AF: 0.640

Gnomad NFE exome AF: 0.611

Gnomad OTH exome AF: 0.628

GnomAD4 exome AF: 0.623 AC: 905821 AN: 1453870 Hom.: 285845 Cov.: 38 AF XY: 0.626 AC XY: 452430 AN XY: 723072

Gnomad4 AFR exome AF: 0.421

Gnomad4 AMR exome AF: 0.770

Gnomad4 ASJ exome AF: 0.535

Gnomad4 EAS exome AF: 0.814

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.638

Gnomad4 NFE exome AF: 0.611

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.580 AC: 88037 AN: 151902 Hom.: 26440 Cov.: 31 AF XY: 0.585 AC XY: 43421 AN XY: 74214

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.681

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.733

Gnomad4 FIN AF: 0.632

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.577

Alfa AF: 0.605 Hom.: 63486

Bravo AF: 0.575

Asia WGS AF: 0.746 AC: 2592 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EMSY-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 10, 2022

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
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.94
Dann	Benign	0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs2508740; hg19: chr11-76227182;