chr1-28987657-T-C

Position:

• chr1-28987657-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001376013.1(EPB41):​c.220T>C​(p.Ser74Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPB41 NM_001376013.1 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.145

Genes affected

EPB41 (HGNC:3377): (erythrocyte membrane protein band 4.1) The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1723252).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.220T>C	p.Ser74Pro	missense_variant	2/21	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9	c.220T>C	p.Ser74Pro	missense_variant	2/21	5	NM_001376013.1	ENSP00000345259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The EPB41 p.S74P variant was not identified in the literature nor was it identified in dbSNP, ClinVar or in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (March 6, 2019, v2.1.1). The p.S74 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;T;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.97	L;L;.;L;.;.;.;.;.;.;L;.;.
MutationTaster	Benign	0.65	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N;N;.;N;.;.;.;.;.;.;N;.;.
REVEL	Benign	0.29
Sift	Uncertain	0.0010	D;T;.;D;.;.;.;.;.;.;T;.;.
Sift4G	Benign	0.13	T;T;.;T;.;.;.;.;.;.;T;.;.
Polyphen		1.0	D;D;.;D;.;.;.;.;.;.;D;.;.
Vest4		0.16
MutPred		0.22		Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);Loss of phosphorylation at S74 (P = 0.0011);
MVP		0.94
MPC		0.25
ClinPred		0.47	T
GERP RS		0.12
Varity_R		0.15
gMVP		0.36

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-29314169;