NM_001376013.1:c.2496+56T>A

Variant names:

• chr1-29112504-T-A
• rs4654390
• NM_001376013.1:c.2496+56T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001376013.1(EPB41):​c.2496+56T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,423,546 control chromosomes in the GnomAD database, including 176,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15103 hom., cov: 30)
  • Exomes 𝑓: 0.50 (161763 hom.)
• Consequence: EPB41 NM_001376013.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.299
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-29112504-T-A is Benign according to our data. Variant chr1-29112504-T-A is described in ClinVar as Benign. ClinVar VariationId is 1236795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.2496+56T>A		intron_variant	Intron 19 of 20	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9	c.2496+56T>A		intron_variant	Intron 19 of 20	5	NM_001376013.1	ENSP00000345259.4

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63508 AN: 151674 Hom.: 15104 Cov.: 30

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.559

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.493

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.499 AC: 635205 AN: 1271754 Hom.: 161763 AF XY: 0.501 AC XY: 322091 AN XY: 642386

African (AFR) AF: 0.180 AC: 5294 AN: 29482

American (AMR) AF: 0.532 AC: 23631 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12314 AN: 24896

East Asian (EAS) AF: 0.469 AC: 18177 AN: 38744

South Asian (SAS) AF: 0.556 AC: 45784 AN: 82408

European-Finnish (FIN) AF: 0.611 AC: 32353 AN: 52946

Middle Eastern (MID) AF: 0.454 AC: 2429 AN: 5354

European-Non Finnish (NFE) AF: 0.500 AC: 469590 AN: 939452

Other (OTH) AF: 0.474 AC: 25633 AN: 54072

GnomAD4 genome AF: 0.418 AC: 63524 AN: 151792 Hom.: 15103 Cov.: 30 AF XY: 0.432 AC XY: 32038 AN XY: 74170

African (AFR) AF: 0.191 AC: 7888 AN: 41394

American (AMR) AF: 0.486 AC: 7394 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.506 AC: 1755 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2299 AN: 5140

South Asian (SAS) AF: 0.559 AC: 2692 AN: 4818

European-Finnish (FIN) AF: 0.630 AC: 6631 AN: 10518

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.493 AC: 33507 AN: 67940

Other (OTH) AF: 0.411 AC: 865 AN: 2104

Alfa AF: 0.331 Hom.: 1012

Bravo AF: 0.391

Asia WGS AF: 0.458 AC: 1593 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.9
DANN	Benign	0.54
PhyloP100		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4654390; hg19: chr1-29439016; COSMIC: COSV58040568; COSMIC: COSV58040568;