chr15-43197459-C-A

Variant names:

• chr15-43197459-C-A
• rs1287191197
• NM_001114134.2:c.1919G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114134.2(EPB42):​c.1919G>T​(p.Arg640Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R640C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB42 NM_001114134.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.645
• Publications: 1 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

ENSG00000285117 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11972743).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114134.2. 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.1919G>T	p.Arg640Leu	missense	Exon 13 of 13	NP_001107606.1	P16452-1
	EPB42	NM_000119.3		c.2009G>T	p.Arg670Leu	missense	Exon 13 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.1919G>T	p.Arg640Leu	missense	Exon 13 of 13	ENSP00000396616.2	P16452-1
	ENSG00000285117	ENST00000563128.6	TSL:3	c.446+4385G>T		intron	N/A	ENSP00000520455.1	A0AAQ5BII2
	EPB42	ENST00000567019.2	TSL:1	n.1425G>T		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.9
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.65
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.034
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
Polyphen		0.0070	B
Vest4		0.20
MutPred		0.59		Loss of catalytic residue at R640 (P = 0.0169)
MVP		0.13
ClinPred		0.095	T
GERP RS		-3.0
Varity_R		0.091
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1287191197; hg19: chr15-43489657;