rs115998465

chr15-43203237-C-Achr15-43203237-C-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3_Moderate PP5

The NM_001114134.2(EPB42):c.1657G>T(p.Glu553Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPB42 NM_001114134.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.11

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 15-43203237-C-A is Pathogenic according to our data. Variant chr15-43203237-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 13237.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB42	NM_001114134.2	c.1657G>T	p.Glu553Ter	stop_gained	11/13	ENST00000441366.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB42	ENST00000441366.7	c.1657G>T	p.Glu553Ter	stop_gained	11/13	1	NM_001114134.2	P1
EPB42	ENST00000567019.2	n.1163G>T		non_coding_transcript_exon_variant	6/8	1
EPB42	ENST00000648595.1	c.1747G>T	p.Glu583Ter	stop_gained	11/13
EPB42	ENST00000540029.5	c.1423G>T	p.Glu475Ter	stop_gained	10/12	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spherocytosis type 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	46
Dann	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.76	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.21, 0.16
GERP RS		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: -3
DS_AL_spliceai		0.44		Position offset: 38

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs115998465; hg19: chr15-43495435;