1-28993490-T-G

Position:

• chr1-28993490-T-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PS1_Moderate PM2 PP5

The ENST00000373800.7(EPB41):​c.2T>G​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41 ENST00000373800.7 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.61

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 13 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 16715
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-28993490-T-G is Pathogenic according to our data. Variant chr1-28993490-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 16714.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.629T>G	p.Met210Arg	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.629T>G	p.Met210Arg	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

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Elliptocytosis 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 1992

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.74	.;.;D;T;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	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	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	.;.;L;.;.;.;.;.;.;L;.;L;.;.;.;.;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.6	.;.;D;N;.;.;.;D;.;D;.;D;.;.;.;.;D;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	.;.;D;D;.;.;.;D;.;D;.;D;.;.;.;.;D;.;.
Sift4G	Uncertain	0.0040	.;.;D;D;.;.;.;D;.;D;.;D;.;.;.;.;D;.;.
Polyphen		0.98	D;.;P;.;.;.;.;D;.;B;.;P;.;.;.;.;P;.;.
Vest4		0.93, 0.84, 0.84, 0.94, 0.94, 0.91
MutPred		0.45		.;.;Gain of disorder (P = 0.0425);.;.;.;.;.;.;Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);Gain of disorder (P = 0.0425);
MVP		0.94
MPC		0.96
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.83

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: rs121434564; hg19: chr1-29320002;