15-43203127-G-T

Position:

• chr15-43203127-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001114134.2(EPB42):​c.1767C>A​(p.His589Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,102 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (9 hom.)
• Consequence: EPB42 NM_001114134.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.30

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014434427).
• BP6: Variant 15-43203127-G-T is Benign according to our data. Variant chr15-43203127-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 316009.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00571 (869/152238) while in subpopulation AFR AF= 0.0199 (827/41530). AF 95% confidence interval is 0.0188. There are 11 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPB42	NM_001114134.2	c.1767C>A	p.His589Gln	missense_variant	11/13	ENST00000441366.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPB42	ENST00000441366.7	c.1767C>A	p.His589Gln	missense_variant	11/13	1	NM_001114134.2	P1
EPB42	ENST00000567019.2	n.1273C>A		non_coding_transcript_exon_variant	6/8	1
EPB42	ENST00000648595.1	c.1857C>A	p.His619Gln	missense_variant	11/13
EPB42	ENST00000540029.5	c.1533C>A	p.His511Gln	missense_variant	10/12	2

Frequencies

GnomAD3 genomes AF: 0.00570 AC: 867 AN: 152120 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00130 AC: 327 AN: 251492 Hom.: 5 AF XY: 0.000993 AC XY: 135 AN XY: 135922

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000538 AC: 787 AN: 1461864 Hom.: 9 Cov.: 32 AF XY: 0.000451 AC XY: 328 AN XY: 727236

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00571 AC: 869 AN: 152238 Hom.: 11 Cov.: 31 AF XY: 0.00529 AC XY: 394 AN XY: 74434

Gnomad4 AFR AF: 0.0199

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00247 Hom.: 5

Bravo AF: 0.00611

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spherocytosis type 5 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Uncertain significance, 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, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.42
DANN	Benign	0.36
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.043	N
MetaRNN	Benign	0.014	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
Polyphen		0.0060	B;B;B;B;.
Vest4		0.16, 0.17, 0.21
MutPred		0.36		.;.;.;Loss of sheet (P = 0.0817);.;
MVP		0.52
ClinPred		0.014	T
GERP RS		-6.8
Varity_R		0.070
gMVP		0.40

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: rs114354377; hg19: chr15-43495325; COSMIC: COSV55749078; COSMIC: COSV55749078;