rs869025285

Variant names:

• chr1-29018388-CGAATCAG-C
• rs869025285
• NM_001376013.1:c.1071_1077delGAATCAG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001376013.1(EPB41):​c.1071_1077delGAATCAG​(p.Asn358ProfsTer18) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41 NM_001376013.1 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.25
• Publications: 0 publications found

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]

EPB41 Gene-Disease associations (from GenCC):

• elliptocytosis 1

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-29018388-CGAATCAG-C is Pathogenic according to our data. Variant chr1-29018388-CGAATCAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 221297.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376013.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41	NM_001376013.1	MANE Select	c.1071_1077delGAATCAG	p.Asn358ProfsTer18	frameshift	Exon 7 of 21	NP_001362942.1
	EPB41	NM_001166005.2		c.1071_1077delGAATCAG	p.Asn358ProfsTer18	frameshift	Exon 7 of 21	NP_001159477.1
	EPB41	NM_001376014.1		c.1071_1077delGAATCAG	p.Asn358ProfsTer18	frameshift	Exon 7 of 20	NP_001362943.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB41	ENST00000343067.9	TSL:5 MANE Select	c.1071_1077delGAATCAG	p.Asn358ProfsTer18	frameshift	Exon 7 of 21	ENSP00000345259.4
	EPB41	ENST00000349460.9	TSL:1	c.1071_1077delGAATCAG	p.Asn358ProfsTer18	frameshift	Exon 7 of 20	ENSP00000317597.8
	EPB41	ENST00000347529.7	TSL:1	c.966_972delGAATCAG	p.Asn323ProfsTer18	frameshift	Exon 6 of 17	ENSP00000290100.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary elliptocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs869025285; hg19: chr1-29344900;