6-158769893-C-G

Variant names:

• chr6-158769893-C-G
• rs142824813
• NM_001111077.2:c.1142G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001111077.2(EZR):​c.1142G>C​(p.Arg381Pro) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R381Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EZR NM_001111077.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

Genes affected

EZR (HGNC:12691): (ezrin) The cytoplasmic peripheral membrane protein encoded by this gene functions as a protein-tyrosine kinase substrate in microvilli. As a member of the ERM protein family, this protein serves as an intermediate between the plasma membrane and the actin cytoskeleton. This protein plays a key role in cell surface structure adhesion, migration and organization, and it has been implicated in various human cancers. A pseudogene located on chromosome 3 has been identified for this gene. Alternatively spliced variants have also been described for this gene. [provided by RefSeq, Jul 2008]

EZR Gene-Disease associations (from GenCC):

• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.747

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111077.2. 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
	EZR	NM_001111077.2	MANE Select	c.1142G>C	p.Arg381Pro	missense	Exon 11 of 14	NP_001104547.1	P15311
	EZR	NM_003379.5		c.1142G>C	p.Arg381Pro	missense	Exon 10 of 13	NP_003370.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZR	ENST00000367075.4	TSL:1 MANE Select	c.1142G>C	p.Arg381Pro	missense	Exon 11 of 14	ENSP00000356042.3	P15311
	EZR	ENST00000337147.11	TSL:1	c.1142G>C	p.Arg381Pro	missense	Exon 10 of 13	ENSP00000338934.7	P15311
	EZR	ENST00000852607.1		c.1280G>C	p.Arg427Pro	missense	Exon 12 of 15	ENSP00000522666.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	0.10
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.057	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.59
Sift	Benign	0.29	T
Sift4G	Benign	0.24	T
Polyphen		0.93	P
Vest4		0.65
MutPred		0.54		Loss of MoRF binding (P = 0.0368)
MVP		0.81
MPC		0.96
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.71
gMVP		0.80
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142824813; hg19: chr6-159190925;