rs121918643

Variant names:

• chr1-158680641-A-G
• rs121918643
• NM_003126.4:c.620T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_003126.4(SPTA1):​c.620T>C​(p.Leu207Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L207L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SPTA1 NM_003126.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 8.95
• Publications: 6 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: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 1-158680641-A-G is Pathogenic according to our data. Variant chr1-158680641-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 12857.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.620T>C	p.Leu207Pro	missense	Exon 5 of 52	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.620T>C	p.Leu207Pro	missense	Exon 5 of 52	ENSP00000495214.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000642 AC: 16 AN: 249322 AF XY: 0.0000444

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000164 AC: 24 AN: 1461640 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727130

African (AFR) AF: 0.000658 AC: 22 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111858

Other (OTH) AF: 0.0000166 AC: 1 AN: 60372

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74446

African (AFR) AF: 0.000722 AC: 30 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000692 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.000787 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000828 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:1

Jul 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 08, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Often seen in cis with the common alpha-LELY allele (PMID: 8068958, 18815189); Also known as spectrin St Louis (PMID: 8068958); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23241237, 8857939, 1541680, 8444470, 18815189, 16150946, 8068958, 8844207, 16730867)

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 207 of the SPTA1 protein (p.Leu207Pro). This variant is present in population databases (rs121918643, gnomAD 0.08%). This missense change has been observed in individual(s) with spherocytosis or pyropoikilocytosis (PMID: 1541680, 8068958, 8444470, 8857939, 18815189). ClinVar contains an entry for this variant (Variation ID: 12857). 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) indicates that this missense variant is expected to disrupt SPTA1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nov 18, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SPTA1 c.620T>C; p.Leu207Pro variant (rs121918643), also known as Spectrin Saint Louis, is reported in the literature as a homozygous and compound heterozygous variant in at least nine individuals affected with either elliptocytosis or hereditary pyropoikilocytosis (Costa 2005, Dalla Venezia 1993, Gallagher 1992, Glele-Kakai 1996). This variant is also reported in ClinVar (Variation ID: 12857). In vitro functional analyses demonstrate reduced protein folding and dimerization (Randles 2013). This variant is found in the African / African-American population with an allele frequency of 0.07% (52/75,030 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). Based on available information, this variant is considered to be pathogenic. REFERENCES Costa DB et al. A novel splicing mutation of the alpha-spectrin gene in the original hereditary pyropoikilocytosis kindred. Blood. 2005 Dec 15. PMID: 16150946 Dalla Venezia N et al. An alpha-spectrin mutation responsible for hereditary elliptocytosis associated in cis with the alpha v/41 polymorphism. Hum Genet. 1993 Feb. PMID: 8444470 Gallagher PG et al. A common type of the spectrin alpha I 46-50a-kD peptide abnormality in hereditary elliptocytosis and pyropoikilocytosis is associated with a mutation distant from the proteolytic cleavage site. Evidence for the functional importance of the triple helical model of spectrin. J Clin Invest. 1992 Mar. PMID: 1541680 Glele-Kakai C et al. Epidemiological studies of spectrin mutations related to hereditary elliptocytosis and spectrin polymorphisms in Benin. Br J Haematol. 1996 Oct. PMID: 8857939 Randles LG et al. Understanding pathogenic single-nucleotide polymorphisms in multidomain proteins--studies of isolated domains are not enough. FEBS J. 2013 Feb. PMID: 23241237

Elliptocytosis 2 Pathogenic:1

Dec 15, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Pyropoikilocytosis, hereditary Pathogenic:1

Dec 15, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.083	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.9
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.91
MPC		0.26
ClinPred		0.72	D
GERP RS		5.3
Varity_R		0.97
gMVP		0.86
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121918643; hg19: chr1-158650431;