Genetic Variant EZR:p.Thr533Lys (chr6-158767077-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001111077.2(EZR):c.1598C>A(p.Thr533Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. T533M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EZR
NM_001111077.2 missense, splice_region

Scores

Splicing: ADA: 0.9087

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.28

Publications

0 publications found

Variant links:

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

EZR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23356164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZR	NM_001111077.2 link	c.1598C>A	p.Thr533Lys	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000367075.4	NP_001104547.1	P15311
EZR	NM_003379.5 link	c.1598C>A	p.Thr533Lys	missense_variant, splice_region_variant	Exon 13 of 13		NP_003370.2	P15311
EZR	XM_011536110.2 link	c.1190C>A	p.Thr397Lys	missense_variant, splice_region_variant	Exon 10 of 10		XP_011534412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZR	ENST00000367075.4 link	c.1598C>A	p.Thr533Lys	missense_variant, splice_region_variant	Exon 14 of 14	1	NM_001111077.2	ENSP00000356042.3		P15311
EZR	ENST00000337147.11 link	c.1598C>A	p.Thr533Lys	missense_variant, splice_region_variant	Exon 13 of 13	1		ENSP00000338934.7		P15311

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727210

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

D;.;D

Eigen

Benign

-0.039

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.68

MutationAssessor

Benign

0.69

N;.;N

PhyloP100

6.3

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.29

Sift

Benign

0.44

T;.;T

Sift4G

Benign

0.85

T;T;T

Polyphen

0.0090

B;.;B

Vest4

0.22

MutPred

0.51

Gain of ubiquitination at T533 (P = 0.0138);Gain of ubiquitination at T533 (P = 0.0138);Gain of ubiquitination at T533 (P = 0.0138);

MVP

0.65

MPC

0.55

ClinPred

0.78

GERP RS

4.4

Varity_R

0.29

gMVP

0.37

Mutation Taster

=60/40

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.79

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.79

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over