chr11-86245279-C-T

Variant names:

• chr11-86245279-C-T
• rs1945363239
• NM_003797.5:c.50C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_003797.5(EED):​c.50C>T​(p.Ala17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EED NM_003797.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.21
• Publications: 0 publications found

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]

EED Gene-Disease associations (from GenCC):

• Cohen-Gibson syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• Weaver syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288809 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 10 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.7345 (below the threshold of 3.09). Trascript score misZ: 2.9199 (below the threshold of 3.09). GenCC associations: The gene is linked to Cohen-Gibson syndrome, Weaver syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10487613).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003797.5. 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
	EED	NM_003797.5	MANE Select	c.50C>T	p.Ala17Val	missense	Exon 1 of 12	NP_003788.2
	EED	NM_001308007.2		c.50C>T	p.Ala17Val	missense	Exon 1 of 13	NP_001294936.1	O75530-2
	EED	NM_001440587.1		c.50C>T	p.Ala17Val	missense	Exon 1 of 12	NP_001427516.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EED	ENST00000263360.11	TSL:1 MANE Select	c.50C>T	p.Ala17Val	missense	Exon 1 of 12	ENSP00000263360.6	O75530-1
	EED	ENST00000351625.10	TSL:1	c.50C>T	p.Ala17Val	missense	Exon 1 of 13	ENSP00000338186.5	O75530-2
	EED	ENST00000327320.8	TSL:1	c.50C>T	p.Ala17Val	missense	Exon 1 of 11	ENSP00000315587.4	O75530-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461278 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111932

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cohen-Gibson syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.040
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.14
Sift	Benign	0.38	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.24		Loss of sheet (P = 0.0457)
MVP		0.69
MPC		0.0014
ClinPred		0.23	T
GERP RS		2.8
PromoterAI		-0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.53
Mutation Taster		=83/17	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: rs1945363239; hg19: chr11-85956321;