6-158776451-T-C

Position:

• chr6-158776451-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001111077.2(EZR):​c.752A>G​(p.Asn251Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000711 in 1,613,692 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (8 hom.)
• Consequence: EZR NM_001111077.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.91

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011818022).
• BP6: Variant 6-158776451-T-C is Benign according to our data. Variant chr6-158776451-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 435111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EZR	NM_001111077.2	c.752A>G	p.Asn251Ser	missense_variant	8/14	ENST00000367075.4	NP_001104547.1
EZR	NM_003379.5	c.752A>G	p.Asn251Ser	missense_variant	7/13		NP_003370.2
EZR	XM_011536110.2	c.344A>G	p.Asn115Ser	missense_variant	4/10		XP_011534412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EZR	ENST00000367075.4	c.752A>G	p.Asn251Ser	missense_variant	8/14	1	NM_001111077.2	ENSP00000356042.3
EZR	ENST00000337147.11	c.752A>G	p.Asn251Ser	missense_variant	7/13	1		ENSP00000338934.7

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152210 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00124 AC: 312 AN: 250684 Hom.: 1 AF XY: 0.00146 AC XY: 198 AN XY: 135462

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00517

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000726 AC: 1061 AN: 1461364 Hom.: 8 Cov.: 31 AF XY: 0.000863 AC XY: 627 AN XY: 726940

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00474

Gnomad4 FIN exome AF: 0.000337

Gnomad4 NFE exome AF: 0.000427

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152328 Hom.: 2 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74484

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000658 Hom.: 1

Bravo AF: 0.000582

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00111 AC: 135

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.000830

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Benign	-0.21
Eigen_PC	Benign	0.0075
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.17	N;.;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.4	D;.;D
REVEL	Uncertain	0.31
Sift	Benign	0.42	T;.;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.030	B;.;B
Vest4		0.42
MVP		0.61
MPC		0.26
ClinPred		0.063	T
GERP RS		4.8
Varity_R		0.59
gMVP		0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs139467617; hg19: chr6-159197483;