rs35719500

Variant names:

• chr15-43208714-G-A
• rs35719500
• NM_001114134.2:c.894C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-43208714-G-A
• chr15-43208714-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001114134.2(EPB42):​c.894C>T​(p.Thr298Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,614,182 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (11 hom.)
• Consequence: EPB42 NM_001114134.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -4.49
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 15-43208714-G-A is Benign according to our data. Variant chr15-43208714-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 255158.
• BP7: Synonymous conserved (PhyloP=-4.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00209 (319/152320) while in subpopulation NFE AF = 0.00385 (262/68028). AF 95% confidence interval is 0.00347. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 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.894C>T	p.Thr298Thr	synonymous	Exon 7 of 13	NP_001107606.1	P16452-1
	EPB42	NM_000119.3		c.984C>T	p.Thr328Thr	synonymous	Exon 7 of 13	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.894C>T	p.Thr298Thr	synonymous	Exon 7 of 13	ENSP00000396616.2	P16452-1
	EPB42	ENST00000567019.2	TSL:1	n.400C>T		non_coding_transcript_exon	Exon 2 of 8
	EPB42	ENST00000648595.1		c.984C>T	p.Thr328Thr	synonymous	Exon 7 of 13	ENSP00000497777.1	P16452-2

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00190 AC: 478 AN: 251424 AF XY: 0.00195

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000970

Gnomad NFE exome AF: 0.00336

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00323 AC: 4719 AN: 1461862 Hom.: 11 Cov.: 32 AF XY: 0.00316 AC XY: 2299 AN XY: 727230

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.000984 AC: 44 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86256

European-Finnish (FIN) AF: 0.00105 AC: 56 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00400 AC: 4447 AN: 1112000

Other (OTH) AF: 0.00209 AC: 126 AN: 60396

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74466

African (AFR) AF: 0.000649 AC: 27 AN: 41572

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00332 Hom.: 0

Bravo AF: 0.00212

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00391

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.052
DANN	Benign	0.46
PhyloP100		-4.5
Mutation Taster		=98/2	polymorphism

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: rs35719500; hg19: chr15-43500912;