rs72721553

Variant names:

• chr15-43210328-C-T
• rs72721553
• NM_001114134.2:c.654+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-43210328-C-T
• chr15-43210328-C-A
• chr15-43210328-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001114134.2(EPB42):​c.654+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,612,534 control chromosomes in the GnomAD database, including 641 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (40 hom., cov: 32)
  • Exomes 𝑓: 0.026 (601 hom.)
• Consequence: EPB42 NM_001114134.2 splice_region, intron
• Scores: Splicing: ADA: 0.00007024
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0750
• Publications: 3 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=-0.66).
• BP6: Variant 15-43210328-C-T is Benign according to our data. Variant chr15-43210328-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0177 (2687/152236) while in subpopulation NFE AF = 0.0272 (1849/68008). AF 95% confidence interval is 0.0262. There are 40 homozygotes in GnomAd4. There are 1373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AD,AR gene

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.654+7G>A		splice_region intron	N/A	NP_001107606.1	P16452-1
	EPB42	NM_000119.3		c.744+7G>A		splice_region intron	N/A	NP_000110.2	P16452-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPB42	ENST00000441366.7	TSL:1 MANE Select	c.654+7G>A		splice_region intron	N/A	ENSP00000396616.2	P16452-1
	EPB42	ENST00000648595.1		c.744+7G>A		splice_region intron	N/A	ENSP00000497777.1	P16452-2
	EPB42	ENST00000540029.5	TSL:2	c.420+7G>A		splice_region intron	N/A	ENSP00000444699.1	F5H563

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2688 AN: 152118 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0253

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0272

Gnomad OTH AF: 0.0201

GnomAD2 exomes AF: 0.0195 AC: 4879 AN: 250672 AF XY: 0.0200

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.0263 AC: 38433 AN: 1460298 Hom.: 601 Cov.: 31 AF XY: 0.0260 AC XY: 18865 AN XY: 726568

African (AFR) AF: 0.00424 AC: 142 AN: 33470

American (AMR) AF: 0.0110 AC: 490 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00609 AC: 159 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39688

South Asian (SAS) AF: 0.0141 AC: 1215 AN: 86232

European-Finnish (FIN) AF: 0.0263 AC: 1383 AN: 52518

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0304 AC: 33762 AN: 1111424

Other (OTH) AF: 0.0208 AC: 1255 AN: 60350

GnomAD4 genome AF: 0.0177 AC: 2687 AN: 152236 Hom.: 40 Cov.: 32 AF XY: 0.0184 AC XY: 1373 AN XY: 74428

African (AFR) AF: 0.00431 AC: 179 AN: 41540

American (AMR) AF: 0.0165 AC: 253 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4822

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0272 AC: 1849 AN: 68008

Other (OTH) AF: 0.0199 AC: 42 AN: 2108

Alfa AF: 0.0231 Hom.: 44

Bravo AF: 0.0166

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.1
DANN	Benign	0.67
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000070
dbscSNV1_RF	Benign	0.0
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: rs72721553; hg19: chr15-43502526;