rs515726212

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001114134.2(EPB42):c.859C>T(p.Arg287Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

EPB42
NM_001114134.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2O:1

Conservation

PhyloP100: 3.16

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 15-43208749-G-A is Pathogenic according to our data. Variant chr15-43208749-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132635.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2 link	c.859C>T	p.Arg287Cys	missense_variant	Exon 7 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.859C>T	p.Arg287Cys	missense_variant	Exon 7 of 13	1	NM_001114134.2	ENSP00000396616.2		P16452-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251138

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000835

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary spherocytosis type 5

Uncertain:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 15, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Dec 15, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM1, PP1, PM3, PP3 -

not specified

Uncertain:1

Dec 05, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EPB42 c.949C>T (p.Arg317Cys) results in a non-conservative amino acid change located in the Transglutaminase-like domain (IPR002931) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251138 control chromosomes in the gnomAD database, including 1 homozygote. c.949C>T has been reported in the literature in individuals affected with hereditary haemolytic anaemia (Kanzaki_1995). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32726712, 29402830, 8547071, 15692067, 8635206). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

.;.;.;D;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

.;D;D;D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

4.2

.;.;.;H;H;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.9

.;.;D;D;.;D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

.;.;D;D;.;D

Sift4G

Pathogenic

0.0

.;.;D;D;D;.

Polyphen

1.0

D;D;D;D;.;.

Vest4

0.97, 0.97, 0.97

MutPred

0.97

.;.;.;Loss of MoRF binding (P = 0.0508);Loss of MoRF binding (P = 0.0508);.;

MVP

0.90

ClinPred

0.99

GERP RS

5.2

Varity_R

0.87

gMVP

0.90

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