NM_001114134.2:c.1318+4C>T

Variant names:

• chr15-43207195-G-A
• rs45498491
• NM_001114134.2:c.1318+4C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001114134.2(EPB42):​c.1318+4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0184 in 1,613,806 control chromosomes in the GnomAD database, including 326 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 0.015 (29 hom., cov: 32)
  • Exomes 𝑓: 0.019 (297 hom.)
• Consequence: EPB42 NM_001114134.2 splice_region, intron
• Scores: Splicing: ADA: 0.00008317
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.938

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-43207195-G-A is Benign according to our data. Variant chr15-43207195-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43207195-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2254/152236) while in subpopulation NFE AF= 0.0212 (1439/68000). AF 95% confidence interval is 0.0203. There are 29 homozygotes in gnomad4. There are 1041 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.1318+4C>T		splice_region_variant, intron_variant	Intron 9 of 12	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.1318+4C>T		splice_region_variant, intron_variant	Intron 9 of 12	1	NM_001114134.2	ENSP00000396616.2

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2255 AN: 152118 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0169 AC: 4222 AN: 250552 Hom.: 50 AF XY: 0.0165 AC XY: 2235 AN XY: 135522

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.0474

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00314

Gnomad FIN exome AF: 0.0161

Gnomad NFE exome AF: 0.0235

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.0188 AC: 27453 AN: 1461570 Hom.: 297 Cov.: 32 AF XY: 0.0184 AC XY: 13373 AN XY: 727102

Gnomad4 AFR exome AF: 0.00358

Gnomad4 AMR exome AF: 0.0144

Gnomad4 ASJ exome AF: 0.0468

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00330

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0174

GnomAD4 genome AF: 0.0148 AC: 2254 AN: 152236 Hom.: 29 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74452

Gnomad4 AFR AF: 0.00327

Gnomad4 AMR AF: 0.0168

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0212

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0204 Hom.: 33

Bravo AF: 0.0146

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0218

EpiControl AF: 0.0232

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spherocytosis type 5 Benign:2

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 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. -

not provided Benign:2

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.3
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000083
dbscSNV1_RF	Benign	0.018
SpliceAI score (max)		0.020		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: rs45498491; hg19: chr15-43499393;