rs114136713

Positions:

• chr15-43211512-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001114134.2(EPB42):​c.453T>C​(p.Asn151Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000871 in 1,612,348 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (4 hom.)
• Consequence: EPB42 NM_001114134.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.370

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 15-43211512-A-G is Benign according to our data. Variant chr15-43211512-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255154.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}. Variant chr15-43211512-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.37 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.002 (304/152336) while in subpopulation AFR AF= 0.00498 (207/41570). AF 95% confidence interval is 0.00442. There are 2 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.453T>C	p.Asn151Asn	synonymous_variant	4/13	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.453T>C	p.Asn151Asn	synonymous_variant	4/13	1	NM_001114134.2	ENSP00000396616.2
EPB42	ENST00000648595.1	c.543T>C	p.Asn181Asn	synonymous_variant	4/13			ENSP00000497777.1
EPB42	ENST00000540029.5	c.219T>C	p.Asn73Asn	synonymous_variant	3/12	2		ENSP00000444699.1
EPB42	ENST00000569204.1	c.117T>C	p.Asn39Asn	synonymous_variant	2/5	3		ENSP00000455489.1

Frequencies

GnomAD3 genomes AF: 0.00200 AC: 304 AN: 152218 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00499

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00133 AC: 335 AN: 251404 Hom.: 2 AF XY: 0.00120 AC XY: 163 AN XY: 135874

Gnomad AFR exome AF: 0.00517

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000906

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.000753 AC: 1100 AN: 1460012 Hom.: 4 Cov.: 30 AF XY: 0.000698 AC XY: 507 AN XY: 726416

Gnomad4 AFR exome AF: 0.00512

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000559

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00200 AC: 304 AN: 152336 Hom.: 2 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74492

Gnomad4 AFR AF: 0.00498

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00266

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spherocytosis type 5 Uncertain:1 Benign:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 26, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.3
DANN	Benign	0.31

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: rs114136713; hg19: chr15-43503710;