6-158767435-T-G

Variant names:

• chr6-158767435-T-G
• rs773034103
• NM_001111077.2:c.1422A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_001111077.2(EZR):​c.1422A>C​(p.Pro474Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P474P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EZR NM_001111077.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.35
• Publications: 0 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EZR	NM_001111077.2	c.1422A>C	p.Pro474Pro	synonymous_variant	Exon 13 of 14	ENST00000367075.4	NP_001104547.1
EZR	NM_003379.5	c.1422A>C	p.Pro474Pro	synonymous_variant	Exon 12 of 13		NP_003370.2
EZR	XM_011536110.2	c.1014A>C	p.Pro338Pro	synonymous_variant	Exon 9 of 10		XP_011534412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EZR	ENST00000367075.4	c.1422A>C	p.Pro474Pro	synonymous_variant	Exon 13 of 14	1	NM_001111077.2	ENSP00000356042.3
EZR	ENST00000337147.11	c.1422A>C	p.Pro474Pro	synonymous_variant	Exon 12 of 13	1		ENSP00000338934.7

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 29 AN: 134674 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000842

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000299

Gnomad ASJ AF: 0.000307

Gnomad EAS AF: 0.000233

Gnomad SAS AF: 0.000256

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000303

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00162 AC: 372 AN: 229422 AF XY: 0.00154

Gnomad AFR exome AF: 0.000333

Gnomad AMR exome AF: 0.000700

Gnomad ASJ exome AF: 0.00136

Gnomad EAS exome AF: 0.000232

Gnomad FIN exome AF: 0.00585

Gnomad NFE exome AF: 0.00203

Gnomad OTH exome AF: 0.00126

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000267 AC: 331 AN: 1240260 Hom.: 0 Cov.: 42 AF XY: 0.000297 AC XY: 184 AN XY: 619462

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000471 AC: 13 AN: 27624

American (AMR) AF: 0.00189 AC: 70 AN: 37054

Ashkenazi Jewish (ASJ) AF: 0.000943 AC: 19 AN: 20158

East Asian (EAS) AF: 0.000149 AC: 4 AN: 26900

South Asian (SAS) AF: 0.000148 AC: 12 AN: 80866

European-Finnish (FIN) AF: 0.00128 AC: 50 AN: 39188

Middle Eastern (MID) AF: 0.00290 AC: 14 AN: 4834

European-Non Finnish (NFE) AF: 0.000146 AC: 139 AN: 954814

Other (OTH) AF: 0.000205 AC: 10 AN: 48822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000215 AC: 29 AN: 134720 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 17 AN XY: 65048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000840 AC: 3 AN: 35706

American (AMR) AF: 0.000299 AC: 4 AN: 13382

Ashkenazi Jewish (ASJ) AF: 0.000307 AC: 1 AN: 3254

East Asian (EAS) AF: 0.000234 AC: 1 AN: 4282

South Asian (SAS) AF: 0.000257 AC: 1 AN: 3898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000303 AC: 19 AN: 62780

Other (OTH) AF: 0.00 AC: 0 AN: 1888

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000732 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.017
DANN	Benign	0.42
PhyloP100		-2.3
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs773034103; hg19: chr6-159188467; COSMIC: COSV51908507; COSMIC: COSV51908507;