rs149249456

Positions:

• chr15-43220737-C-T

Variant summary

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

The NM_000119.3(EPB42):​c.89G>A​(p.Ser30Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 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 0.0012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: EPB42 NM_000119.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -0.519

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=0.0057874024).
• BP6: Variant 15-43220737-C-T is Benign according to our data. Variant chr15-43220737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255156.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00107 (1560/1460356) while in subpopulation SAS AF= 0.00137 (118/86252). AF 95% confidence interval is 0.00117. There are 5 homozygotes in gnomad4_exome. There are 787 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.10+79G>A		intron_variant		ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.10+79G>A		intron_variant		1	NM_001114134.2	ENSP00000396616.2
EPB42	ENST00000648595.1	c.89G>A	p.Ser30Asn	missense_variant	1/13			ENSP00000497777.1
EPB42	ENST00000540029.5	c.10+79G>A		intron_variant		2		ENSP00000444699.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 177 AN: 151408 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.00159 AC: 399 AN: 250884 Hom.: 2 AF XY: 0.00158 AC XY: 214 AN XY: 135646

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00108

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00107 AC: 1560 AN: 1460356 Hom.: 5 Cov.: 34 AF XY: 0.00108 AC XY: 787 AN XY: 726514

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00137

Gnomad4 FIN exome AF: 0.00934

Gnomad4 NFE exome AF: 0.000776

Gnomad4 OTH exome AF: 0.000912

GnomAD4 genome AF: 0.00117 AC: 177 AN: 151528 Hom.: 0 Cov.: 30 AF XY: 0.00146 AC XY: 108 AN XY: 74012

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00736

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000955 Hom.: 0

Bravo AF: 0.000484

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.000981

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spherocytosis type 5 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 05, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	EPB42: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.9
DANN	Uncertain	0.99
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.74	T
PrimateAI	Benign	0.31	T
Polyphen		0.0020	B;B
ClinPred		0.020	T
GERP RS		0.69
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs149249456; hg19: chr15-43512935;