rs149249456

Variant names:

• chr15-43220737-C-T
• rs149249456
• NM_001114134.2:c.10+79G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000119.3(EPB42):​c.89G>A​(p.Ser30Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,884 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.0012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: EPB42 NM_000119.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.519
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057874024).
• BP6: Variant 15-43220737-C-T is Benign according to our data. Variant chr15-43220737-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255156.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (177/151528) while in subpopulation NFE AF = 0.00119 (81/67884). AF 95% confidence interval is 0.000983. There are 0 homozygotes in GnomAd4. There are 108 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000119.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	NM_001114134.2	MANE Select	c.10+79G>A		intron	N/A	NP_001107606.1	P16452-1
	EPB42	NM_000119.3		c.89G>A	p.Ser30Asn	missense	Exon 1 of 13	NP_000110.2	P16452-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	ENST00000441366.7	TSL:1 MANE Select	c.10+79G>A		intron	N/A	ENSP00000396616.2	P16452-1
	EPB42	ENST00000648595.1		c.89G>A	p.Ser30Asn	missense	Exon 1 of 13	ENSP00000497777.1	P16452-2
	EPB42	ENST00000540029.5	TSL:2	c.10+79G>A		intron	N/A	ENSP00000444699.1	F5H563

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 177 AN: 151408 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000481

GnomAD2 exomes AF: 0.00159 AC: 399 AN: 250884 AF XY: 0.00158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0100

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00107 AC: 1560 AN: 1460356 Hom.: 5 Cov.: 34 AF XY: 0.00108 AC XY: 787 AN XY: 726514

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.000649 AC: 29 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26102

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86252

European-Finnish (FIN) AF: 0.00934 AC: 492 AN: 52652

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.000776 AC: 862 AN: 1111454

Other (OTH) AF: 0.000912 AC: 55 AN: 60322

GnomAD4 genome AF: 0.00117 AC: 177 AN: 151528 Hom.: 0 Cov.: 30 AF XY: 0.00146 AC XY: 108 AN XY: 74012

African (AFR) AF: 0.000121 AC: 5 AN: 41282

American (AMR) AF: 0.000460 AC: 7 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5108

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4792

European-Finnish (FIN) AF: 0.00736 AC: 77 AN: 10468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 67884

Other (OTH) AF: 0.000476 AC: 1 AN: 2102

Alfa AF: 0.000928 Hom.: 1

Bravo AF: 0.000484

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.000981

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary spherocytosis type 5 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	2.9
DANN	Uncertain	0.99
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.74	T
PhyloP100		-0.52
PrimateAI	Benign	0.31	T
Polyphen		0.0020	B
ClinPred		0.020	T
GERP RS		0.69
PromoterAI		-0.029	Neutral
gMVP		0.14
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs149249456; hg19: chr15-43512935;