15-43206339-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001114134.2(EPB42):c.1609G>A(p.Ala537Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,610,698 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

EPB42
NM_001114134.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 0.665

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

hereditary spherocytosis type 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPB42 links:

ENSG00000285117 (HGNC:):

ENSG00000285117 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0075327754).

BP6

Variant 15-43206339-C-T is Benign according to our data. Variant chr15-43206339-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 132637.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00104 (158/152242) while in subpopulation NFE AF = 0.00176 (120/68002). AF 95% confidence interval is 0.00151. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2 link	c.1609G>A	p.Ala537Thr	missense_variant	Exon 10 of 13	ENST00000441366.7	NP_001107606.1	P16452-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7 link	c.1609G>A	p.Ala537Thr	missense_variant	Exon 10 of 13	1	NM_001114134.2	ENSP00000396616.2		P16452-1
ENSG00000285117	ENST00000563128.6 link	c.142G>A	p.Ala48Thr	missense_variant	Exon 1 of 4	3		ENSP00000520455.1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

158

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000566

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00107

AC:

267

AN:

248638

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000232

Gnomad ASJ exome

AF:

0.00252

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00173

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00128

AC:

1862

AN:

1458456

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

947

AN XY:

724856

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33416

American (AMR)

AF:

0.000269

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00250

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39614

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53300

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00146

AC:

1621

AN:

1109314

Other (OTH)

AF:

0.00116

AC:

AN:

60212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

198

298

397

496

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00104

AC:

158

AN:

152242

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41552

American (AMR)

AF:

0.000784

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000566

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00176

AC:

120

AN:

68002

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00111

AC:

135

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00191

EpiControl

AF:

0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 5

Uncertain:2

Aug 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The EPB42 c.1699G>A; p.Ala567Thr variant (rs45495503, ClinVar variation ID: 132637), is reported in the literature in one individual affected with hemolytic anemia and alpha thalassemia, this individual also carried a splice donor variant in EPB42 and two copies of the 3.7kb alpha globin deletion (Maciag 2009). This variant is found in the general population with an overall allele frequency of 0.1% (303/279,988 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is neutral (REVEL: 0.105). Due to limited information, the clinical significance of this EPB42 variant is uncertain at this time. References: Maciag M et al. The use of real-time PCR technique in the detection of novel protein 4.2 gene mutations that coexist with thalassaemia alpha in a single patient. Eur J Haematol. 2009 Oct. PMID: 19508687 -

Nov 10, 2016

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1Benign:1

Sep 14, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.16

.;.;.;T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.61

.;T;T;T;T

M_CAP

Benign

0.062

MetaRNN

Benign

0.0075

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.2

.;.;.;M;.

PhyloP100

0.67

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

.;.;N;N;.

REVEL

Benign

0.10

Sift

Benign

0.24

.;.;T;T;.

Sift4G

Benign

0.28

.;.;T;T;T

Polyphen

0.024

B;B;B;B;.

Vest4

0.093, 0.10, 0.12

MVP

0.77

ClinPred

0.012

GERP RS

3.7

Varity_R

0.043

gMVP

0.66

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over