1-28993489-A-G

Position:

• chr1-28993489-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The ENST00000373800.7(EPB41):​c.1A>G​(p.Met1?) variant causes a start lost 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41 ENST00000373800.7 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.69

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 Pathogenic. Variant got 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in ENST00000373800.7 (EPB41) was described as [Pathogenic] in ClinVar as 16714
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-28993489-A-G is Pathogenic according to our data. Variant chr1-28993489-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 618091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.628A>G	p.Met210Val	missense_variant	3/21	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9	c.628A>G	p.Met210Val	missense_variant	3/21	5	NM_001376013.1	ENSP00000345259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 12, 2019	PVS1, PM2, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.34	.;.;T;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.057	D
MetaRNN	Uncertain	0.57	D;D;T;D;D;D;D;D;D;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.99	.;.;L;.;.;.;.;.;.;L;.;L;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.8	.;.;N;N;.;.;.;N;.;N;.;N;.;.;.;.;N;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.64	.;.;T;D;.;.;.;T;.;T;.;T;.;.;.;.;T;.;.
Sift4G	Benign	0.89	.;.;T;T;.;.;.;T;.;T;.;T;.;.;.;.;T;.;.
Polyphen		0.097	B;.;B;.;.;.;.;P;.;B;.;B;.;.;.;.;P;.;.
Vest4		0.69, 0.76, 0.75, 0.72, 0.68, 0.69
MutPred		0.34		.;.;Loss of catalytic residue at M210 (P = 8e-04);.;.;.;.;.;.;Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);Loss of catalytic residue at M210 (P = 8e-04);
MVP		0.87
MPC		0.74
ClinPred		0.89	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.44

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: rs1557948192; hg19: chr1-29320001;