rs121918643

Variant summary

Our verdict is Uncertain significance. Variant got 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).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 8.95

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 Uncertain_significance. Variant got 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 id is 12857.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.620T>C	p.Leu207Pro	missense_variant	5/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.620T>C	p.Leu207Pro	missense_variant	5/52		NM_003126.4	P1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000642

AC:

AN:

249322

Hom.:

AF XY:

0.0000444

AC XY:

AN XY:

135242

show subpopulations

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 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:

0.0000164

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000197

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000254

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000787

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000828

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 31, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	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 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2023	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, 16150946, 1541680, 8444470, 18815189) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 23, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. -

Elliptocytosis 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2005

- -

Pyropoikilocytosis, hereditary

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 15, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Pathogenic

0.25

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.70

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.97

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Uncertain

-0.083

MutationAssessor

Pathogenic

3.3

M;M

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0010

D;.

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.91

MPC

0.26

ClinPred

0.72

GERP RS

5.3

Varity_R

0.97

gMVP

0.86

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

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