rs3103004

Variant names:

• chr6-158784657-G-A
• rs3103004
• NM_001111077.2:c.538C>T

Your query was ambiguous. Multiple possible variants found:

• chr6-158784657-G-A
• chr6-158784657-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001111077.2(EZR):​c.538C>T​(p.Arg180Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000498 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (0 hom.)
• Consequence: EZR NM_001111077.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.236
• Publications: 7 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22374552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZR	NM_001111077.2	c.538C>T	p.Arg180Cys	missense_variant	Exon 6 of 14	ENST00000367075.4	NP_001104547.1
EZR	NM_003379.5	c.538C>T	p.Arg180Cys	missense_variant	Exon 5 of 13		NP_003370.2
EZR	XM_011536110.2	c.130C>T	p.Arg44Cys	missense_variant	Exon 2 of 10		XP_011534412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZR	ENST00000367075.4	c.538C>T	p.Arg180Cys	missense_variant	Exon 6 of 14	1	NM_001111077.2	ENSP00000356042.3
EZR	ENST00000337147.11	c.538C>T	p.Arg180Cys	missense_variant	Exon 5 of 13	1		ENSP00000338934.7
EZR	ENST00000476189.1	n.810C>T		non_coding_transcript_exon_variant	Exon 7 of 8	3

Frequencies

GnomAD3 genomes AF: 0.000519 AC: 79 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000956

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251432 AF XY: 0.000280

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000495 AC: 724 AN: 1461802 Hom.: 0 Cov.: 32 AF XY: 0.000466 AC XY: 339 AN XY: 727204

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000590 AC: 656 AN: 1111930

Other (OTH) AF: 0.000480 AC: 29 AN: 60394

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.000605 AC XY: 45 AN XY: 74346

African (AFR) AF: 0.000145 AC: 6 AN: 41438

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000956 AC: 65 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000619 Hom.: 1

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000313 AC: 38

EpiCase AF: 0.000327

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 19, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.8	M;.;M
PhyloP100		0.24
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.5	D;.;D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.46	P;.;P
Vest4		0.19
MVP		0.84
MPC		0.45
ClinPred		0.20	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.38
gMVP		0.56
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3103004; hg19: chr6-159205689; COSMIC: COSV61455466;