chr1-28987675-T-G

Variant names:

• chr1-28987675-T-G
• rs942222753
• ENST00000373800:c.-470T>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001376022.1(EPB41):​c.-390T>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.0000041 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: EPB41 NM_001376022.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37404907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPB41	NM_001376013.1	c.238T>G	p.Ser80Ala	missense_variant	Exon 2 of 21	ENST00000343067.9	NP_001362942.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPB41	ENST00000343067.9	c.238T>G	p.Ser80Ala	missense_variant	Exon 2 of 21	5	NM_001376013.1	ENSP00000345259.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.;.;T;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.0	L;L;.;L;.;.;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N;N;.;N;.;.;.;.;.;.;N;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;.;D;.;.;.;.;.;.;D;.;.
Sift4G	Benign	0.079	T;T;.;T;.;.;.;.;.;.;T;.;.
Polyphen		0.98	D;D;.;D;.;.;.;.;.;.;D;.;.
Vest4		0.59
MutPred		0.27		Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);Loss of phosphorylation at S80 (P = 0.0011);
MVP		0.95
MPC		0.70
ClinPred		0.92	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs942222753; hg19: chr1-29314187;