11-86245347-A-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003797.5(EED):c.114+4A>C variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.0000491 in 1,608,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: EED NM_003797.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9987
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.31

Genes affected

EED (HGNC:3188): (embryonic ectoderm development) This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein interacts with enhancer of zeste 2, the cytoplasmic tail of integrin beta7, immunodeficiency virus type 1 (HIV-1) MA protein, and histone deacetylase proteins. This protein mediates repression of gene activity through histone deacetylation, and may act as a specific regulator of integrin function. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 11-86245347-A-C is Benign according to our data. Variant chr11-86245347-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2848984.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EED	NM_003797.5	c.114+4A>C		splice_donor_region_variant, intron_variant		ENST00000263360.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EED	ENST00000263360.11	c.114+4A>C		splice_donor_region_variant, intron_variant		1	NM_003797.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151502 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000621 AC: 15 AN: 241456 Hom.: 0 AF XY: 0.0000533 AC XY: 7 AN XY: 131314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000206

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: 0.0000566

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.0000487 AC: 71 AN: 1456500 Hom.: 0 Cov.: 29 AF XY: 0.0000386 AC XY: 28 AN XY: 724760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000433

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.0000528 AC: 8 AN: 151618 Hom.: 0 Cov.: 30 AF XY: 0.0000675 AC XY: 5 AN XY: 74108

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000893 Hom.: 0

Bravo AF: 0.0000491

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cohen-Gibson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 25, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. This variant has not been reported in the literature in individuals affected with EED-related conditions. This variant is present in population databases (rs202074959, gnomAD 0.02%). This sequence change falls in intron 1 of the EED gene. It does not directly change the encoded amino acid sequence of the EED protein. It affects a nucleotide within the consensus splice site. -

EED-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2023

This variant is classified as likely 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	-0.31
Cadd	Benign	22
Dann	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.030		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: rs202074959; hg19: chr11-85956389;