6-158767517-G-A

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.1345-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,565,678 control chromosomes in the GnomAD database, including 11,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1124 hom., cov: 31)
  • Exomes 𝑓: 0.12 (10621 hom.)
• Consequence: EZR NM_001111077.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002669
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.82

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 (BayesDel_noAF=-0.81).
• BP6: Variant 6-158767517-G-A is Benign according to our data. Variant chr6-158767517-G-A is described in ClinVar as [Benign]. Clinvar id is 3055436.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EZR	NM_001111077.2	c.1345-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000367075.4
EZR	NM_003379.5	c.1345-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
EZR	XM_011536110.2	c.937-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EZR	ENST00000367075.4	c.1345-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001111077.2	P1
EZR	ENST00000337147.11	c.1345-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17739 AN: 152004 Hom.: 1122 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0803

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.111 AC: 23783 AN: 214118 Hom.: 1565 AF XY: 0.114 AC XY: 13147 AN XY: 115344

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0578

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.000818

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.116

GnomAD4 exome AF: 0.119 AC: 167585 AN: 1413556 Hom.: 10621 Cov.: 36 AF XY: 0.119 AC XY: 82872 AN XY: 698388

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.0589

Gnomad4 ASJ exome AF: 0.127

Gnomad4 EAS exome AF: 0.000995

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.184

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.117 AC: 17759 AN: 152122 Hom.: 1124 Cov.: 31 AF XY: 0.116 AC XY: 8638 AN XY: 74362

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0802

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.113

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.117

Alfa AF: 0.119 Hom.: 981

Bravo AF: 0.108

Asia WGS AF: 0.0620 AC: 216 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EZR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	7.5
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0060
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: rs3212310; hg19: chr6-159188549;