rs77809780

Variant names:

• chr15-43220797-G-A
• rs77809780
• NM_001114134.2:c.10+19C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-43220797-G-A
• chr15-43220797-G-C

Variant summary

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

The NM_000119.3(EPB42):​c.29C>T​(p.Ser10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,612,802 control chromosomes in the GnomAD database, including 353 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (177 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (176 hom.)
• Consequence: EPB42 NM_000119.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.865
• Publications: 6 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 (MetaRNN=0.0026146472).
• BP6: Variant 15-43220797-G-A is Benign according to our data. Variant chr15-43220797-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000119.3. 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.10+19C>T		intron	N/A	NP_001107606.1
	EPB42	NM_000119.3		c.29C>T	p.Ser10Leu	missense	Exon 1 of 13	NP_000110.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	ENST00000441366.7	TSL:1 MANE Select	c.10+19C>T		intron	N/A	ENSP00000396616.2
	EPB42	ENST00000648595.1		c.29C>T	p.Ser10Leu	missense	Exon 1 of 13	ENSP00000497777.1
	EPB42	ENST00000540029.5	TSL:2	c.10+19C>T		intron	N/A	ENSP00000444699.1

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4050 AN: 152000 Hom.: 175 Cov.: 31

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0340

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00971 AC: 2433 AN: 250496 AF XY: 0.00807

Gnomad AFR exome AF: 0.0843

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000378

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00385 AC: 5629 AN: 1460684 Hom.: 176 Cov.: 33 AF XY: 0.00355 AC XY: 2580 AN XY: 726734

African (AFR) AF: 0.0876 AC: 2933 AN: 33474

American (AMR) AF: 0.00456 AC: 204 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26134

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

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52240

Middle Eastern (MID) AF: 0.00607 AC: 35 AN: 5768

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1112002

Other (OTH) AF: 0.0115 AC: 694 AN: 60388

GnomAD4 genome AF: 0.0267 AC: 4058 AN: 152118 Hom.: 177 Cov.: 31 AF XY: 0.0254 AC XY: 1886 AN XY: 74350

African (AFR) AF: 0.0874 AC: 3626 AN: 41474

American (AMR) AF: 0.0103 AC: 158 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0341 AC: 176 AN: 5162

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68006

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0108 Hom.: 135

Bravo AF: 0.0308

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0833 AC: 367

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0111 AC: 1349

Asia WGS AF: 0.0430 AC: 148 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.6
DANN	Uncertain	1.0
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.88	T
PhyloP100		0.86
PrimateAI	Benign	0.40	T
Polyphen		0.010	B
ClinPred		0.028	T
GERP RS		-1.0
PromoterAI		-0.0072	Neutral
gMVP		0.44
Mutation Taster		=99/1	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: rs77809780; hg19: chr15-43512995; COSMIC: COSV55750862;