chr15-43206339-C-T

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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 0.0010 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 6 hom. )

Consequence

EPB42
NM_001114134.2 missense

Scores

1
18

Clinical Significance

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

Conservation

PhyloP100: 0.665
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]

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=0.0075327754).
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 id is 132637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPB42NM_001114134.2 linkc.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
EPB42ENST00000441366.7 linkc.1609G>A p.Ala537Thr missense_variant Exon 10 of 13 1 NM_001114134.2 ENSP00000396616.2 P16452-1
ENSG00000285117ENST00000563128.5 linkn.143G>A non_coding_transcript_exon_variant Exon 1 of 4 3 ENSP00000520455.1

Frequencies

GnomAD3 genomes
AF:
0.00104
AC:
158
AN:
152124
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.00107
AC:
267
AN:
248638
Hom.:
0
AF XY:
0.00104
AC XY:
140
AN XY:
134506
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 SAS exome
AF:
0.0000655
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.:
6
Cov.:
32
AF XY:
0.00131
AC XY:
947
AN XY:
724856
show subpopulations
Gnomad4 AFR exome
AF:
0.000209
Gnomad4 AMR exome
AF:
0.000269
Gnomad4 ASJ exome
AF:
0.00250
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00148
Gnomad4 NFE exome
AF:
0.00146
Gnomad4 OTH exome
AF:
0.00116
GnomAD4 genome
AF:
0.00104
AC:
158
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.000887
AC XY:
66
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.000217
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00202
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000566
Gnomad4 NFE
AF:
0.00176
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.00161
Hom.:
1
Bravo
AF:
0.00102
TwinsUK
AF:
0.00135
AC:
5
ALSPAC
AF:
0.00104
AC:
4
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00174
AC:
15
ExAC
AF:
0.00111
AC:
135
Asia WGS
AF:
0.000289
AC:
1
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
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
11
DANN
Benign
0.97
DEOGEN2
Benign
0.16
.;.;.;T;.
Eigen
Benign
-0.36
Eigen_PC
Benign
-0.32
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.61
.;T;T;T;T
M_CAP
Benign
0.062
D
MetaRNN
Benign
0.0075
T;T;T;T;T
MetaSVM
Benign
-0.67
T
MutationAssessor
Uncertain
2.2
.;.;.;M;.
PrimateAI
Benign
0.26
T
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
T
GERP RS
3.7
Varity_R
0.043
gMVP
0.66

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

LitVar

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

Other links and lift over

dbSNP: rs45495503; hg19: chr15-43498537; COSMIC: COSV105177368; COSMIC: COSV105177368; API