15-43220797-G-C

Variant names:

• chr15-43220797-G-C
• rs77809780
• NM_001114134.2:c.10+19C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114134.2(EPB42):​c.10+19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EPB42 NM_001114134.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.865
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3026018).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB42	NM_001114134.2	c.10+19C>G		intron_variant	Intron 1 of 12	ENST00000441366.7	NP_001107606.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB42	ENST00000441366.7	c.10+19C>G		intron_variant	Intron 1 of 12	1	NM_001114134.2	ENSP00000396616.2
EPB42	ENST00000648595.1	c.29C>G	p.Ser10Trp	missense_variant	Exon 1 of 13			ENSP00000497777.1
EPB42	ENST00000540029.5	c.10+19C>G		intron_variant	Intron 1 of 11	2		ENSP00000444699.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460688 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726736

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	3.9
DANN	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.42	T
PhyloP100		0.86
PrimateAI	Benign	0.42	T
Polyphen		0.99	D;D
MutPred		0.26		Loss of disorder (P = 0);Loss of disorder (P = 0);
ClinPred		0.98	D
GERP RS		-1.0
PromoterAI		-0.0030	Neutral
gMVP		0.52

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

Other links and lift over

dbSNP: rs77809780; hg19: chr15-43512995;