6-158767096-A-G

Variant names:

• chr6-158767096-A-G
• rs2242318
• NM_001111077.2:c.1597-18T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001111077.2(EZR):​c.1597-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.707 in 1,613,162 control chromosomes in the GnomAD database, including 416,358 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.66 (34245 hom., cov: 31)
  • Exomes 𝑓: 0.71 (382113 hom.)
• Consequence: EZR NM_001111077.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0380
• Publications: 16 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111077.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZR	NM_001111077.2	MANE Select	c.1597-18T>C		intron	N/A	NP_001104547.1
	EZR	NM_003379.5		c.1597-18T>C		intron	N/A	NP_003370.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EZR	ENST00000367075.4	TSL:1 MANE Select	c.1597-18T>C		intron	N/A	ENSP00000356042.3
	EZR	ENST00000337147.11	TSL:1	c.1597-18T>C		intron	N/A	ENSP00000338934.7

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100023 AN: 151862 Hom.: 34211 Cov.: 31

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.494

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.743

Gnomad OTH AF: 0.622

GnomAD2 exomes AF: 0.622 AC: 154861 AN: 248852 AF XY: 0.635

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.633

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.820

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.624

GnomAD4 exome AF: 0.712 AC: 1039757 AN: 1461182 Hom.: 382113 Cov.: 45 AF XY: 0.710 AC XY: 516261 AN XY: 726906

African (AFR) AF: 0.596 AC: 19944 AN: 33462

American (AMR) AF: 0.369 AC: 16501 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.631 AC: 16476 AN: 26120

East Asian (EAS) AF: 0.163 AC: 6457 AN: 39698

South Asian (SAS) AF: 0.636 AC: 54840 AN: 86224

European-Finnish (FIN) AF: 0.819 AC: 43725 AN: 53382

Middle Eastern (MID) AF: 0.532 AC: 3066 AN: 5764

European-Non Finnish (NFE) AF: 0.754 AC: 838548 AN: 1111492

Other (OTH) AF: 0.666 AC: 40200 AN: 60348

GnomAD4 genome AF: 0.659 AC: 100125 AN: 151980 Hom.: 34245 Cov.: 31 AF XY: 0.654 AC XY: 48581 AN XY: 74282

African (AFR) AF: 0.605 AC: 25062 AN: 41426

American (AMR) AF: 0.494 AC: 7542 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2175 AN: 3470

East Asian (EAS) AF: 0.170 AC: 876 AN: 5164

South Asian (SAS) AF: 0.628 AC: 3023 AN: 4816

European-Finnish (FIN) AF: 0.819 AC: 8653 AN: 10566

Middle Eastern (MID) AF: 0.561 AC: 165 AN: 294

European-Non Finnish (NFE) AF: 0.743 AC: 50498 AN: 67958

Other (OTH) AF: 0.622 AC: 1313 AN: 2110

Alfa AF: 0.689 Hom.: 7439

Bravo AF: 0.622

Asia WGS AF: 0.442 AC: 1539 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.29
DANN	Benign	0.66
PhyloP100		0.038
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 41

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

Other links and lift over

dbSNP: rs2242318; hg19: chr6-159188128; COSMIC: COSV51912913; COSMIC: COSV51912913;