rs1554273605

Positions:

• chr6-158789290-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001111077.2(EZR):​c.94C>G​(p.Gln32Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EZR NM_001111077.2 missense, splice_region
• Scores: Splicing: ADA: 0.9610
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZR	NM_001111077.2	c.94C>G	p.Gln32Glu	missense_variant, splice_region_variant	3/14	ENST00000367075.4	NP_001104547.1
EZR	NM_003379.5	c.94C>G	p.Gln32Glu	missense_variant, splice_region_variant	2/13		NP_003370.2
EZR	XM_011536110.2	c.57C>G	p.Ile19Met	missense_variant, splice_region_variant	1/10		XP_011534412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZR	ENST00000367075.4	c.94C>G	p.Gln32Glu	missense_variant, splice_region_variant	3/14	1	NM_001111077.2	ENSP00000356042.3
EZR	ENST00000337147.11	c.94C>G	p.Gln32Glu	missense_variant, splice_region_variant	2/13	1		ENSP00000338934.7
EZR	ENST00000476189.1	n.200C>G		splice_region_variant, non_coding_transcript_exon_variant	3/8	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 11, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;.;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	M;.;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.68
Sift	Benign	0.030	D;D;D
Sift4G	Benign	0.14	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.84
MutPred		0.67		Loss of ubiquitination at K27 (P = 0.0853);Loss of ubiquitination at K27 (P = 0.0853);Loss of ubiquitination at K27 (P = 0.0853);
MVP		0.85
MPC		1.1
ClinPred		0.98	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.69
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: rs1554273605; hg19: chr6-159210322;