chr1-28987675-T-C

Variant names:

• chr1-28987675-T-C
• rs942222753
• NM_001376013.1:c.238T>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001376013.1(EPB41):​c.238T>C​(p.Ser80Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: EPB41 NM_001376013.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

Genes affected

EPB41 (HGNC:3377): (erythrocyte membrane protein band 4.1) The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.238T>C	p.Ser80Pro	missense_variant	Exon 2 of 21	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9	c.238T>C	p.Ser80Pro	missense_variant	Exon 2 of 21	5	NM_001376013.1	ENSP00000345259.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251240 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EPB41 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001166005.1, and corresponds to NM_004437.3:c.-470T>C in the primary transcript. This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 80 of the EPB41 protein (p.Ser80Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with EPB41-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;D;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.0	L;L;.;L;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.4	N;N;.;N;.;.;.;.;.;.;D;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	D;D;.;D;.;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0030	D;D;.;D;.;.;.;.;.;.;D;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.
Vest4		0.74
MutPred		0.24		Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);
MVP		0.96
MPC		0.88
ClinPred		0.79	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.50

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: rs942222753; hg19: chr1-29314187;