rs766257622

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001376013.1(EPB41):c.532G>A(p.Glu178Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000991 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

EPB41
NM_001376013.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33

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 -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15382996).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00000958 (14/1461576) while in subpopulation EAS AF= 0.000126 (5/39674). AF 95% confidence interval is 0.0000491. There are 0 homozygotes in gnomad4_exome. There are 10 alleles in male gnomad4_exome subpopulation. Median coverage is 31. 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.532G>A	p.Glu178Lys	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.532G>A	p.Glu178Lys	missense_variant	Exon 3 of 21	5	NM_001376013.1	ENSP00000345259.4		P11171-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152156

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251300

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461576

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EPB41 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001166005.1, and corresponds to NM_004437.3:c.-96G>A in the primary transcript. This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 178 of the EPB41 protein (p.Glu178Lys). This variant is present in population databases (rs766257622, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with EPB41-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

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

Eigen

Benign

-0.088

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.90

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

M_CAP

Benign

0.024

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.43

MutationAssessor

Benign

1.4

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.23

Sift

Benign

0.071

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

Sift4G

Benign

0.19

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

Polyphen

0.0

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

Vest4

0.21

MutPred

0.30

Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);Gain of methylation at E178 (P = 0.0031);

MVP

0.91

MPC

0.23

ClinPred

0.24

GERP RS

5.2

Varity_R

0.17

gMVP

0.38

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