rs61343376

Positions:

• chr15-43208779-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001114134.2(EPB42):​c.833-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,613,598 control chromosomes in the GnomAD database, including 1,101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (580 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (521 hom.)
• Consequence: EPB42 NM_001114134.2 splice_region, intron
• Scores: Splicing: ADA: 0.0004688
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.16

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]

EPB42 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 15-43208779-T-C is Benign according to our data. Variant chr15-43208779-T-C is described in ClinVar as [Benign]. Clinvar id is 255157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.833-4A>G		splice_region_variant, intron_variant		ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.833-4A>G		splice_region_variant, intron_variant		1	NM_001114134.2	ENSP00000396616.2

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7215 AN: 151944 Hom.: 571 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0340

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0150 AC: 3739 AN: 249390 Hom.: 244 AF XY: 0.0119 AC XY: 1609 AN XY: 135196

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0401

Gnomad SAS exome AF: 0.00369

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.00589 AC: 8602 AN: 1461536 Hom.: 521 Cov.: 32 AF XY: 0.00532 AC XY: 3867 AN XY: 727060

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.00731

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.00378

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0477 AC: 7252 AN: 152062 Hom.: 580 Cov.: 32 AF XY: 0.0450 AC XY: 3346 AN XY: 74352

Gnomad4 AFR AF: 0.162

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0341

Gnomad4 SAS AF: 0.00355

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0342

Alfa AF: 0.0243 Hom.: 105

Bravo AF: 0.0549

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000712

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spherocytosis type 5 Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified Benign:1

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_noAF	Benign	-0.85
CADD	Benign	0.035
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs61343376; hg19: chr15-43500977;