chr15-43215195-C-T

Variant names:

• chr15-43215195-C-T
• rs1042168
• NM_001114134.2:c.330G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001114134.2(EPB42):​c.330G>A​(p.Ala110Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0077 in 1,614,172 control chromosomes in the GnomAD database, including 644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (336 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (308 hom.)
• Consequence: EPB42 NM_001114134.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.36
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 15-43215195-C-T is Benign according to our data. Variant chr15-43215195-C-T is described in ClinVar as Benign. ClinVar VariationId is 255153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 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.330G>A	p.Ala110Ala	synonymous	Exon 3 of 13	NP_001107606.1
	EPB42	NM_000119.3		c.420G>A	p.Ala140Ala	synonymous	Exon 3 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.330G>A	p.Ala110Ala	synonymous	Exon 3 of 13	ENSP00000396616.2
	EPB42	ENST00000648595.1		c.420G>A	p.Ala140Ala	synonymous	Exon 3 of 13	ENSP00000497777.1
	EPB42	ENST00000540029.5	TSL:2	c.196+1073G>A		intron	N/A	ENSP00000444699.1

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5524 AN: 152162 Hom.: 334 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0292

GnomAD2 exomes AF: 0.0121 AC: 3040 AN: 251484 AF XY: 0.00984

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.0401

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00471 AC: 6887 AN: 1461892 Hom.: 308 Cov.: 32 AF XY: 0.00429 AC XY: 3122 AN XY: 727246

African (AFR) AF: 0.122 AC: 4098 AN: 33480

American (AMR) AF: 0.00566 AC: 253 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26136

East Asian (EAS) AF: 0.0269 AC: 1066 AN: 39700

South Asian (SAS) AF: 0.00344 AC: 297 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.000239 AC: 266 AN: 1112012

Other (OTH) AF: 0.0134 AC: 807 AN: 60396

GnomAD4 genome AF: 0.0364 AC: 5543 AN: 152280 Hom.: 336 Cov.: 32 AF XY: 0.0344 AC XY: 2564 AN XY: 74470

African (AFR) AF: 0.122 AC: 5059 AN: 41532

American (AMR) AF: 0.0118 AC: 180 AN: 15308

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

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5182

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68024

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.0140 Hom.: 156

Bravo AF: 0.0416

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000711

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	-0.74
CADD	Benign	11
DANN	Benign	0.48
PhyloP100		-1.4
PromoterAI		-0.026	Neutral
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: rs1042168; hg19: chr15-43507393; COSMIC: COSV55748750; COSMIC: COSV55748750;