15-43210328-C-T

Position:

chr15-43210328-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001114134.2(EPB42):c.654+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,612,534 control chromosomes in the GnomAD database, including 641 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 32)

Exomes 𝑓: 0.026 ( 601 hom. )

Consequence

EPB42
NM_001114134.2 splice_region, intron

Scores

Splicing: ADA: 0.00007024

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0750

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]

EPB42 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 15-43210328-C-T is Benign according to our data. Variant chr15-43210328-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43210328-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0177 (2687/152236) while in subpopulation NFE AF= 0.0272 (1849/68008). AF 95% confidence interval is 0.0262. There are 40 homozygotes in gnomad4. There are 1373 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2 linkuse as main transcript	c.654+7G>A		splice_region_variant, intron_variant		ENST00000441366.7	NP_001107606.1	P16452-1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
EPB42	ENST00000441366.7 linkuse as main transcript	c.654+7G>A	splice_region_variant, intron_variant	1	NM_001114134.2	ENSP00000396616.2	P16452-1
EPB42	ENST00000648595.1 linkuse as main transcript	c.744+7G>A	splice_region_variant, intron_variant			ENSP00000497777.1	P16452-2
EPB42	ENST00000540029.5 linkuse as main transcript	c.420+7G>A	splice_region_variant, intron_variant	2		ENSP00000444699.1	F5H563
EPB42	ENST00000569204.1 linkuse as main transcript	c.214-877G>A	intron_variant	3		ENSP00000455489.1	H3BPV8

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2688

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00435

Gnomad AMI

AF:

0.0253

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.0265

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0272

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0195

AC:

4879

AN:

250672

Hom.:

AF XY:

0.0200

AC XY:

2710

AN XY:

135568

show subpopulations

Gnomad AFR exome

AF:

0.00462

Gnomad AMR exome

AF:

0.0102

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0146

Gnomad FIN exome

AF:

0.0253

Gnomad NFE exome

AF:

0.0291

Gnomad OTH exome

AF:

0.0174

GnomAD4 exome

AF:

0.0263

AC:

38433

AN:

1460298

Hom.:

601

Cov.:

AF XY:

0.0260

AC XY:

18865

AN XY:

726568

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.0110

Gnomad4 ASJ exome

AF:

0.00609

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0141

Gnomad4 FIN exome

AF:

0.0263

Gnomad4 NFE exome

AF:

0.0304

Gnomad4 OTH exome

AF:

0.0208

GnomAD4 genome

AF:

0.0177

AC:

2687

AN:

152236

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1373

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00431

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00871

Gnomad4 FIN

AF:

0.0265

Gnomad4 NFE

AF:

0.0272

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0221

Hom.:

Bravo

AF:

0.0166

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spherocytosis type 5

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.1

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000070

dbscSNV1_RF

Benign

0.0

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over