rs1042168

Positions:

• chr15-43215195-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001114134.2(EPB42):​c.330G>A​(p.Ala110=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,614,172 control chromosomes in the GnomAD database, including 644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (336 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (308 hom.)
• Consequence: EPB42 NM_001114134.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.36

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-43215195-C-T is Benign according to our data. Variant chr15-43215195-C-T is described in ClinVar as [Benign]. Clinvar id is 255153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-43215195-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB42	NM_001114134.2	c.330G>A	p.Ala110=	synonymous_variant	3/13	ENST00000441366.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB42	ENST00000441366.7	c.330G>A	p.Ala110=	synonymous_variant	3/13	1	NM_001114134.2	P1
EPB42	ENST00000648595.1	c.420G>A	p.Ala140=	synonymous_variant	3/13
EPB42	ENST00000540029.5	c.196+1073G>A		intron_variant		2
EPB42	ENST00000569204.1			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5524 AN: 152162 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0121 AC: 3040 AN: 251484 Hom.: 144 AF XY: 0.00984 AC XY: 1338 AN XY: 135912

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0401

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00471 AC: 6887 AN: 1461892 Hom.: 308 Cov.: 32 AF XY: 0.00429 AC XY: 3122 AN XY: 727246

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.00566

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0269

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000239

Gnomad4 OTH exome AF: 0.0134

GnomAD4 genome AF: 0.0364 AC: 5543 AN: 152280 Hom.: 336 Cov.: 32 AF XY: 0.0344 AC XY: 2564 AN XY: 74470

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0294

Alfa AF: 0.0106 Hom.: 95

Bravo AF: 0.0416

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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	-0.74
CADD	Benign	11
DANN	Benign	0.48

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1042168; hg19: chr15-43507393; COSMIC: COSV55748750; COSMIC: COSV55748750;