NM_003797.5:c.12G>T

Variant names:

• chr11-86245241-G-T
• rs548903343
• NM_003797.5:c.12G>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.12G>T​(p.Arg4Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: EED NM_003797.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64
• 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=0.21074116).

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.12G>T	p.Arg4Ser	missense	Exon 1 of 12	NP_003788.2
	EED	NM_001308007.2		c.12G>T	p.Arg4Ser	missense	Exon 1 of 13	NP_001294936.1	O75530-2
	EED	NM_001440587.1		c.12G>T	p.Arg4Ser	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.12G>T	p.Arg4Ser	missense	Exon 1 of 12	ENSP00000263360.6	O75530-1
	EED	ENST00000351625.10	TSL:1	c.12G>T	p.Arg4Ser	missense	Exon 1 of 13	ENSP00000338186.5	O75530-2
	EED	ENST00000327320.8	TSL:1	c.12G>T	p.Arg4Ser	missense	Exon 1 of 11	ENSP00000315587.4	O75530-3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	0.079
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.17	N
REVEL	Uncertain	0.30
Sift	Benign	0.034	D
Sift4G	Benign	0.97	T
Polyphen		0.46	P
Vest4		0.089
MutPred		0.26		Gain of glycosylation at R4 (P = 0.0175)
MVP		0.79
MPC		0.0012
ClinPred		0.51	D
GERP RS		4.6
PromoterAI		-0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.65
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: rs548903343; hg19: chr11-85956283;