1-158662793-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003126.4(SPTA1):c.2373C>A(p.Asp791Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,022 control chromosomes in the GnomAD database, including 97 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 0.015 ( 52 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 45 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:7

Conservation

PhyloP100: 1.99

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0041577816).

BP6

Variant 1-158662793-G-T is Benign according to our data. Variant chr1-158662793-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12859.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Likely_pathogenic=1, Benign=2}. Variant chr1-158662793-G-T is described in Lovd as [Pathogenic].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.2373C>A	p.Asp791Glu	missense_variant	Exon 17 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.2373C>A	p.Asp791Glu	missense_variant	Exon 17 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2192

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0497

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00681

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.00362

AC:

904

AN:

249438

Hom.:

AF XY:

0.00265

AC XY:

359

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.00206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00160

AC:

2335

AN:

1461764

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

1001

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0551

Gnomad4 AMR exome

AF:

0.00271

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000108

Gnomad4 OTH exome

AF:

0.00369

GnomAD4 genome

AF:

0.0145

AC:

2208

AN:

152258

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1070

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0500

Gnomad4 AMR

AF:

0.00680

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00214

Hom.:

Bravo

AF:

0.0168

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0478

AC:

186

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.00431

AC:

521

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Jul 01, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spectrin Jendouba is a missense alteration in alpha spectrin that has long been associated with elliptocytosis. In our opinion, Spectrin Jendouba erroneously is classified as benign due to automated filters and strict cut-offs to classify alterations with MAF >5% as benign because this alteration has a high MAF in some subpopulations in population databases. For hereditary elliptocytosis a higher than 5% MAF may be acceptable, particularly in persons with ancestry from the malaria belt. Because it usually causes little other clinical manifestations, HE is under diagnosed, but is estimated to be 1 in 2000 – 1 in 4000 worldwide and up to 1 in 50 in African/African American sub-populations (UpToDate). Therefore, we suggest an exception from BA1 for SPTA1 gene based on the likely enrichment of disorder-causing alleles in ancestral populations where malaria is endemic. There is heterozygous advantage, particularly in genes affecting RBCs (Lelliott 2015 PMID 26215182), similar to what is suggested by the Hemoglobinopathy Variant Curation Expert Panel (Kountouris 2022 PMID 34510646). In regards to the specific pathogenicity of Spectrin Jendouba, there are numerous reports in the literature of its association with elliptocytosis and other RBC membranopathies if co-inherited with pathogenic alterations (Niss 2016 PMID 27667160, Alloisio 1992 PMID: 1638030, Kim 2021 PMID 33556202, Van Vuren 2019 PMID: 31723846). Most hereditary elliptocytosis variants are found in the C-terminal of helices 3. (Alloisio 1992 PMID: 1638030). This alteration occurs in helix 3, distant from the spectrin head-to-head self-association site resulting in a mild defect in spectrin dimer self-association. Our internal data including peripheral blood smear review showed all instances of Spectrin Jendouba presented with some red blood cell abnormality (mainly elliptocytes, however, when found with alphaLELY, also poikilocytes, spherocytes). Overall, based on the available evidence, we classify this variant as likely pathogenic. -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Elliptocytosis 2

Pathogenic:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aug 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:1

Jan 05, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asp791Glu variant in SPTA1 is classified as likely benign because it has been identified in 4.97% (2060/41414) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), including 51 homozygotes. In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -

Hereditary spherocytosis type 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pyropoikilocytosis, hereditary;C1851741:Elliptocytosis 2;C2678338:Hereditary spherocytosis type 3

Benign:1

Apr 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Pyropoikilocytosis, hereditary

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.42

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

.;D

MetaRNN

Benign

0.0042

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Benign

0.45

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.12

Sift

Benign

0.18

T;.

Sift4G

Benign

0.072

T;.

Polyphen

0.72

P;P

Vest4

0.52

MutPred

0.60

Gain of disorder (P = 0.1156);Gain of disorder (P = 0.1156);

MVP

0.54

MPC

0.22

ClinPred

0.040

GERP RS

1.4

Varity_R

0.078

gMVP

0.073

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