NM_003126.4:c.2373C>A

Variant names:

• chr1-158662793-G-T
• rs7418956
• NM_003126.4:c.2373C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 12/21 in silico tools predict 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:7
• Conservation: PhyloP100: 1.99
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• elliptocytosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine
• pyropoikilocytosis, hereditary

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• 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	c.2373C>A	p.Asp791Glu	missense_variant	Exon 17 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2	c.2373C>A	p.Asp791Glu	missense_variant	Exon 17 of 52		NM_003126.4	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2192 AN: 152140 Hom.: 51 Cov.: 32

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

GnomAD2 exomes AF: 0.00362 AC: 904 AN: 249438 AF XY: 0.00265

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 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.: 45 Cov.: 31 AF XY: 0.00138 AC XY: 1001 AN XY: 727184

African (AFR) AF: 0.0551 AC: 1842 AN: 33452

American (AMR) AF: 0.00271 AC: 121 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5756

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1111970

Other (OTH) AF: 0.00369 AC: 223 AN: 60392

GnomAD4 genome AF: 0.0145 AC: 2208 AN: 152258 Hom.: 52 Cov.: 32 AF XY: 0.0144 AC XY: 1070 AN XY: 74444

African (AFR) AF: 0.0500 AC: 2076 AN: 41536

American (AMR) AF: 0.00680 AC: 104 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00622 Hom.: 51

Bravo AF: 0.0168

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0478 AC: 186

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.00431 AC: 521

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign: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. -

Sep 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Elliptocytosis 2 Pathogenic:1 Benign:1

Aug 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		2.0
PrimateAI	Benign	0.45	T
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	T
GERP RS		1.4
Varity_R		0.078
gMVP		0.073
Mutation Taster		=94/6	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: rs7418956; hg19: chr1-158632583;