6-158767377-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001111077.2(EZR):c.1480G>C(p.Ala494Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 1,613,982 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A494V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (64 hom.)
• Consequence: EZR NM_001111077.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0230

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026685).
• BP6: Variant 6-158767377-C-G is Benign according to our data. Variant chr6-158767377-C-G is described in ClinVar as [Benign]. Clinvar id is 776178.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZR	NM_001111077.2	c.1480G>C	p.Ala494Pro	missense_variant	13/14	ENST00000367075.4
EZR	NM_003379.5	c.1480G>C	p.Ala494Pro	missense_variant	12/13
EZR	XM_011536110.2	c.1072G>C	p.Ala358Pro	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZR	ENST00000367075.4	c.1480G>C	p.Ala494Pro	missense_variant	13/14	1	NM_001111077.2	P1
EZR	ENST00000337147.11	c.1480G>C	p.Ala494Pro	missense_variant	12/13	1		P1

Frequencies

GnomAD3 genomes AF: 0.0161 AC: 2455 AN: 152014 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00419 AC: 1052 AN: 251286 Hom.: 39 AF XY: 0.00324 AC XY: 440 AN XY: 135842

Gnomad AFR exome AF: 0.0576

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00165 AC: 2407 AN: 1461850 Hom.: 64 Cov.: 40 AF XY: 0.00138 AC XY: 1003 AN XY: 727234

Gnomad4 AFR exome AF: 0.0587

Gnomad4 AMR exome AF: 0.00326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.0161 AC: 2456 AN: 152132 Hom.: 55 Cov.: 32 AF XY: 0.0157 AC XY: 1171 AN XY: 74352

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.00640

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.0194

ESP6500AA AF: 0.0554 AC: 244

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00505 AC: 613

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.9
Dann	Benign	0.91
DEOGEN2	Uncertain	0.49	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.97	N;.;N
REVEL	Benign	0.18
Sift	Benign	0.27	T;.;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.18
MVP		0.54
MPC		0.43
ClinPred		0.0011	T
GERP RS		-4.3
Varity_R		0.054
gMVP		0.23

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: rs2230143; hg19: chr6-159188409; COSMIC: COSV51913183; COSMIC: COSV51913183;