chr1-158678434-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong
The NM_003126.4(SPTA1):c.779T>C(p.Leu260Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,700 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 (★★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
SPTA1
NM_003126.4 missense
NM_003126.4 missense
Scores
8
9
1
Clinical Significance
Conservation
PhyloP100: 8.48
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 1-158678434-A-G is Pathogenic according to our data. Variant chr1-158678434-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-158678434-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTA1 | NM_003126.4 | c.779T>C | p.Leu260Pro | missense_variant | 6/52 | ENST00000643759.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTA1 | ENST00000643759.2 | c.779T>C | p.Leu260Pro | missense_variant | 6/52 | NM_003126.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 249130Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135138
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461496Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727058
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2022 | Observed in individuals with hereditary elliptocytosis, however these individuals were not screened for variants in other genes associated with hereditary elliptocytosis (Glele-Kakai et al., 1996); Published functional studies demonstrate that L260P increased the stability of the closed dimer state, reduced tetramer assembly, and resulted in membrane destabilization (Randles et al., 2013; Harper et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 3597773, 23974198, 2794061, 8857939, 31130284, 23241237, 32641076) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | Experimental studies have shown that this missense change affects SPTA1 function (PMID: 23974198). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 12844). This missense change has been observed in individual(s) with autosomal dominant hereditary elliptocytosis and autosomal recessive hereditary pyropoikilocytosis (PMID: 2794061, 8857939, 18815189, 31130284, 32641076). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121918634, gnomAD 0.02%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 260 of the SPTA1 protein (p.Leu260Pro). - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 24, 2023 | - - |
Elliptocytosis 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1989 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Mar 29, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Uncertain
D;.
Polyphen
D;D
Vest4
MutPred
Loss of stability (P = 0.024);Loss of stability (P = 0.024);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at