rs45594632

Variant names:

• chr15-43207238-G-A
• rs45594632
• NM_001114134.2:c.1279C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001114134.2(EPB42):​c.1279C>T​(p.Arg427Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00469 in 1,614,094 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (19 hom.)
• Consequence: EPB42 NM_001114134.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.53

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009778529).
• BP6: Variant 15-43207238-G-A is Benign according to our data. Variant chr15-43207238-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255148.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00295 (449/152224) while in subpopulation AMR AF= 0.0051 (78/15284). AF 95% confidence interval is 0.00419. There are 1 homozygotes in gnomad4. There are 204 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.1279C>T	p.Arg427Cys	missense_variant	Exon 9 of 13	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.1279C>T	p.Arg427Cys	missense_variant	Exon 9 of 13	1	NM_001114134.2	ENSP00000396616.2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 449 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00447

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00292 AC: 734 AN: 251270 Hom.: 0 AF XY: 0.00286 AC XY: 389 AN XY: 135844

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00327

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00476

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00487 AC: 7115 AN: 1461870 Hom.: 19 Cov.: 32 AF XY: 0.00474 AC XY: 3450 AN XY: 727238

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00434

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74430

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00447

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00418 Hom.: 2

Bravo AF: 0.00314

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00272 AC: 330

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00507

EpiControl AF: 0.00522

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EPB42: BP4, BS2 -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spherocytosis type 5 Uncertain:1 Benign:1

Jun 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.55	.;.;.;D;.
Eigen	Benign	-0.048
Eigen_PC	Benign	0.029
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.84	.;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0098	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;.;.;M;.
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.5	.;.;D;D;.
REVEL	Benign	0.13
Sift	Benign	0.073	.;.;T;T;.
Sift4G	Benign	0.22	.;.;T;T;T
Polyphen		0.46	P;P;P;P;.
Vest4		0.27, 0.29, 0.31
MVP		0.68
ClinPred		0.044	T
GERP RS		5.0
Varity_R		0.19
gMVP		0.70

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

Other links and lift over

dbSNP: rs45594632; hg19: chr15-43499436; COSMIC: COSV99038329; COSMIC: COSV99038329;