rs201231112

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001376013.1(EPB41):c.520G>A(p.Glu174Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000806 in 1,613,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

EPB41
NM_001376013.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89

Variant links:

Genes affected

EPB41 (HGNC:3377): (erythrocyte membrane protein band 4.1) The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Oct 2009]

EPB41 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.008530289).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000525 (8/152288) while in subpopulation EAS AF= 0.00135 (7/5192). AF 95% confidence interval is 0.000632. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41	NM_001376013.1 link	c.520G>A	p.Glu174Lys	missense_variant	Exon 3 of 21	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9 link	c.520G>A	p.Glu174Lys	missense_variant	Exon 3 of 21	5	NM_001376013.1	ENSP00000345259.4		P11171-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251290

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00223

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000835

AC:

122

AN:

1461364

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727006

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00292

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000190

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Elliptocytosis 1

Uncertain:1

Nov 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EPB41 c.520G>A; p.Glu174Lys variant (rs201231112), also known as c.-108G>A for NM_004437.4, is reported in the literature in one neonatal individual affected with hyperbilirubinemia and G6PD-deficiency (Lin 2022); however, additional evidence of pathogenicity was not provided and the clinical significance of p.Glu174Lys in that patientâ€™s phenotype is uncertain. This variant is found in the East Asian population with an allele frequency of 0.2% (41/19954 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.212). This variant is found in an alternate transcript of EPB41 that is expressed in whole blood (Genotype-Tissue Expression project). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Lin F et al. Clinical features and genetic variations of severe neonatal hyperbilirubinemia: Five case reports. World J Clin Cases. 2022 Jul 16. PMID: 36051115 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.14

T;.;.;T;.;.;.;.;.;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.25

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D;D;.;D;D;D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.0085

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.7

L;L;.;L;.;.;.;.;L;.;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.33

N;N;.;N;.;.;.;.;N;.;.

REVEL

Benign

0.21

Sift

Benign

0.48

T;T;.;T;.;.;.;.;T;.;.

Sift4G

Benign

0.53

T;T;.;T;.;.;.;.;T;.;.

Polyphen

0.0

B;B;.;B;.;.;.;.;B;.;.

Vest4

0.18

MVP

0.90

MPC

0.26

ClinPred

0.12

GERP RS

3.8

Varity_R

0.086

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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