1-158685289-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_003126.4(SPTA1):c.83G>A(p.Arg28His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

SPTA1 (HGNC:11272): (spectrin alpha, erythrocytic 1) This gene encodes a member of a family of molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. The encoded protein is primarily composed of 22 spectrin repeats which are involved in dimer formation. It forms a component of the erythrocyte plasma membrane. Mutations in this gene result in a variety of hereditary red blood cell disorders, including elliptocytosis-2, pyropoikilocytosis, and spherocytosis, type 3. [provided by RefSeq, Aug 2017]

SPTA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 3) in uniprot entity SPTA1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003126.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-158685290-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.959

PP5

Variant 1-158685289-C-T is Pathogenic according to our data. Variant chr1-158685289-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158685289-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.83G>A	p.Arg28His	missense_variant	Exon 2 of 52	ENST00000643759.2	NP_003117.2	P02549-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2 link	c.83G>A	p.Arg28His	missense_variant	Exon 2 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

246770

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134086

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461658

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 28 of the SPTA1 protein (p.Arg28His). This variant is present in population databases (rs121918641, gnomAD 0.02%). This missense change has been observed in individual(s) with elliptocytosis and/or pyropoikilocytosis (PMID: 1679439, 2328319). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg22His. ClinVar contains an entry for this variant (Variation ID: 12856). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPTA1 protein function. Experimental studies have shown that this missense change affects SPTA1 function (PMID: 18218854). This variant disrupts the p.Arg28 amino acid residue in SPTA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1679439, 18218854, 28090778, 29729090, 31286676). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jun 20, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional characterization of protein harboring the R28H variant indicate no detectable binding affinity to the beta subunit, thus abolishing tetramer formation (PMID: 18218854); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R22H; This variant is associated with the following publications: (PMID: 2043465, 3692477, 28102861, 29936674, 30317022, 1679439, 7819065, 27667160, 31723846, 31038472, 33210974, 10680706, 31589614, 31694722, 33074480, 33726816, 34132406, 2328319, 18218854, 7074218, 8435324, 28090778, 29729090) -

May 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SPTA1 c.83G>A; p.Arg28His variant (rs121918641), also known as p.Arg22His, is reported in the literature in at least 12 individuals from a multigenerational family affected with either elliptocytosis or pyropoikilocytosis (Garbarz 1990). It has also been reported on opposite chromosomes from the complex alpha-LELY allele in one individual with severe elliptocytosis (Baklouti 1991), as well as five individuals affected with elliptocytosis and pyropoikilocytosis from two unrelated families (Coetzer 1991). In vitro functional analyses show this variant abrogates spectrin tetramerization (Gaetani 2008). This variant is reported in ClinVar (Variation ID: 12856) and is found predominantly in the African/African-American population with an allele frequency of 0.03% (7/24,196 alleles) in the Genome Aggregation Database. Additionally, other amino acid substitutions at this codon (p.Arg28Leu, p.Arg28Ser, and p.Arg28Cys) have been reported in individuals with elliptocytosis and are considered pathogenic (Coetzer 1991, Floyd 1991). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.419). Based on available information, this variant is considered to be pathogenic. References: Baklouti F et al. Occurrence of the alpha I 22 Arg----His (CGT----CAT) spectrin mutation in Tunisia: potential association with severe elliptopoikilocytosis. Br J Haematol. 1991 May. PMID: 2043465. Coetzer TL et al. Four different mutations in codon 28 of alpha spectrin are associated with structurally and functionally abnormal spectrin alpha I/74 in hereditary elliptocytosis. J Clin Invest. 1991 Sep. PMID: 1679439. Floyd PB et al. Heterogeneity of the molecular basis of hereditary pyropoikilocytosis and hereditary elliptocytosis associated with increased levels of the spectrin alpha I/74-kilodalton tryptic peptide. Blood. 1991 Sep 01. PMID: 1878597. Gaetani M et al. Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site. Blood. 2008 Jun 15. PMID: 18218854. Garbarz M et al. Hereditary pyropoikilocytosis and elliptocytosis in a white French family with the spectrin alpha I/74 variant related to a CGT to CAT codon change (Arg to His) at position 22 of the spectrin alpha I domain. Blood. 1990 Apr 15. PMID: 2328319. -

Jan 04, 2024

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Elliptocytosis 2

Pathogenic:3

Jul 08, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PM5 moderated, PM6 moderated, PP1 strong -

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83G>A (p.Arg28His) missense variant (published as R22H due to alternate nomenclature) in SPTA1 gene has been reported previously in a multigenerational family with either hereditary elliptocytosis (HE) or hereditary pyropoikilocytosis (Garbarz et al., 1990). Functional characterization of protein harboring the R28H variant indicate no detectable binding affinity to the beta subunit, thus abolishing tetramer formation (Gaetani et al., 2008). This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 28 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg28His in SPTA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

May 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pyropoikilocytosis, hereditary

Pathogenic:2

Feb 23, 2023

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18218854). In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.85). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012856). Different missense changes at the same codon (p.Arg28Cys, p.Arg28Leu) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012853, VCV000012855). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Prenatal anemia

Pathogenic:1

Apr 09, 2019

Rare Disease Group, Clinical Genetics, Karolinska Institutet

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SPTA1-related disorder

Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPTA1 c.83G>A variant is predicted to result in the amino acid substitution p.Arg28His. This variant along with other missense changes at the same amino acid position (p.Arg28Leu and p.Arg28Cys) have been shown to be causative for hereditary elliptocytosis in the heterozygous state (Garbarz et al. 1990. PubMed ID: 2328319; Coetzer et al. 1991. PubMed ID: 1679439). This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-4.3

D;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.93

Loss of MoRF binding (P = 0.0658);Loss of MoRF binding (P = 0.0658);

MVP

0.80

MPC

0.24

ClinPred

1.0

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.39

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over