rs61343376

Variant names:

• chr15-43208779-T-C
• rs61343376
• NM_001114134.2:c.833-4A>G

Variant summary

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

The NM_001114134.2(EPB42):​c.833-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 1,613,598 control chromosomes in the GnomAD database, including 1,101 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (580 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (521 hom.)
• Consequence: EPB42 NM_001114134.2 splice_region, intron
• Scores: Splicing: ADA: 0.0004688
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.16
• Publications: 2 publications found

Genes affected

EPB42 (HGNC:3381): (erythrocyte membrane protein band 4.2) Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of protein 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

EPB42 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary spherocytosis

  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=-0.85).
• BP6: Variant 15-43208779-T-C is Benign according to our data. Variant chr15-43208779-T-C is described in ClinVar as Benign. ClinVar VariationId is 255157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114134.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	NM_001114134.2	MANE Select	c.833-4A>G		splice_region intron	N/A	NP_001107606.1
	EPB42	NM_000119.3		c.923-4A>G		splice_region intron	N/A	NP_000110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	ENST00000441366.7	TSL:1 MANE Select	c.833-4A>G		splice_region intron	N/A	ENSP00000396616.2
	EPB42	ENST00000567019.2	TSL:1	n.339-4A>G		splice_region intron	N/A
	EPB42	ENST00000648595.1		c.923-4A>G		splice_region intron	N/A	ENSP00000497777.1

Frequencies

GnomAD3 genomes AF: 0.0475 AC: 7215 AN: 151944 Hom.: 571 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0340

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0340

GnomAD2 exomes AF: 0.0150 AC: 3739 AN: 249390 AF XY: 0.0119

Gnomad AFR exome AF: 0.162

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.0401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000428

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.00589 AC: 8602 AN: 1461536 Hom.: 521 Cov.: 32 AF XY: 0.00532 AC XY: 3867 AN XY: 727060

African (AFR) AF: 0.166 AC: 5540 AN: 33474

American (AMR) AF: 0.00731 AC: 327 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26132

East Asian (EAS) AF: 0.0269 AC: 1067 AN: 39698

South Asian (SAS) AF: 0.00378 AC: 326 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53290

Middle Eastern (MID) AF: 0.00818 AC: 47 AN: 5746

European-Non Finnish (NFE) AF: 0.000237 AC: 263 AN: 1111858

Other (OTH) AF: 0.0161 AC: 974 AN: 60376

GnomAD4 genome AF: 0.0477 AC: 7252 AN: 152062 Hom.: 580 Cov.: 32 AF XY: 0.0450 AC XY: 3346 AN XY: 74352

African (AFR) AF: 0.162 AC: 6705 AN: 41462

American (AMR) AF: 0.0156 AC: 238 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.0341 AC: 176 AN: 5164

South Asian (SAS) AF: 0.00355 AC: 17 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 67982

Other (OTH) AF: 0.0342 AC: 72 AN: 2108

Alfa AF: 0.0235 Hom.: 137

Bravo AF: 0.0549

Asia WGS AF: 0.0480 AC: 166 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000712

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hereditary spherocytosis type 5 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.035
DANN	Benign	0.55
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00047
dbscSNV1_RF	Benign	0.0020
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: rs61343376; hg19: chr15-43500977;