rs1131692173

chr11-86268501-A-Cchr11-86268501-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_003797.5(EED):c.906A>C(p.Arg302Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R302G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EED NM_003797.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.02

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_pathogenic. Variant got 8 ACMG points.

• PM1: In a region_of_interest Required for interaction with the matrix protein MA of HIV-1 (size 140) in uniprot entity EED_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003797.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-86268499-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 430645.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75
• PP5: Variant 11-86268501-A-C is Pathogenic according to our data. Variant chr11-86268501-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 430643.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-86268501-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EED	NM_003797.5	c.906A>C	p.Arg302Ser	missense_variant	9/12	ENST00000263360.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EED	ENST00000263360.11	c.906A>C	p.Arg302Ser	missense_variant	9/12	1	NM_003797.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cohen-Gibson syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Uncertain	0.45
Sift	Benign	0.10	T;T;T
Sift4G	Uncertain	0.056	T;T;D
Polyphen		0.75	P;D;D
Vest4		0.76
MutPred		0.55		Loss of catalytic residue at R302 (P = 0.0028);Loss of catalytic residue at R302 (P = 0.0028);Loss of catalytic residue at R302 (P = 0.0028);
MVP		0.88
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1131692173; hg19: chr11-85979543;