chr15-43207238-G-A

Position:

chr15-43207238-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001114134.2(EPB42):c.1279C>T(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,614,094 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 19 hom. )

Consequence

EPB42
NM_001114134.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.53

Variant links:

Genes affected

EPB42 (HGNC:3381): (erythrocyte membrane protein band 4.2) Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of protein 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EPB42 links:

EPB42 (HGNC:):

EPB42 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009778529).

BP6

Variant 15-43207238-G-A is Benign according to our data. Variant chr15-43207238-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255148.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00295 (449/152224) while in subpopulation AMR AF= 0.0051 (78/15284). AF 95% confidence interval is 0.00419. There are 1 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2 linkuse as main transcript	c.1279C>T	p.Arg427Cys	missense_variant	9/13	ENST00000441366.7	NP_001107606.1	P16452-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7 linkuse as main transcript	c.1279C>T	p.Arg427Cys	missense_variant	9/13	1	NM_001114134.2	ENSP00000396616.2		P16452-1

Frequencies

GnomAD3 genomes

AF:

0.00295

AC:

449

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.000472

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00447

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00292

AC:

734

AN:

251270

Hom.:

AF XY:

0.00286

AC XY:

389

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00476

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00487

AC:

7115

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00474

AC XY:

3450

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.00349

Gnomad4 ASJ exome

AF:

0.00256

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000499

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.00586

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00295

AC:

449

AN:

152224

Hom.:

Cov.:

AF XY:

0.00274

AC XY:

204

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00510

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.000472

Gnomad4 NFE

AF:

0.00447

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00418

Hom.:

Bravo

AF:

0.00314

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00272

AC:

330

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00507

EpiControl

AF:

0.00522

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	EPB42: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

Hereditary spherocytosis type 5

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

.;.;.;D;.

Eigen

Benign

-0.048

Eigen_PC

Benign

0.029

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.84

.;T;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0098

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;.;.;M;.

PrimateAI

Benign

0.28

PROVEAN

Pathogenic

-4.5

.;.;D;D;.

REVEL

Benign

0.13

Sift

Benign

0.073

.;.;T;T;.

Sift4G

Benign

0.22

.;.;T;T;T

Polyphen

0.46

P;P;P;P;.

Vest4

0.27, 0.29, 0.31

MVP

0.68

ClinPred

0.044

GERP RS

5.0

Varity_R

0.19

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over