chr1-158681595-G-GCAA
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM4_SupportingPP5_Very_Strong
The NM_003126.4(SPTA1):c.460_462dupTTG(p.Leu154dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_003126.4 conservative_inframe_insertion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000302 AC: 46AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000763 AC: 19AN: 249160Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135152
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461584Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24AN XY: 727096
GnomAD4 genome AF: 0.000302 AC: 46AN: 152242Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20AN XY: 74438
ClinVar
Submissions by phenotype
not provided Pathogenic:7
SPTA1: PM3:Very Strong, PM1, PM2, PP1:Moderate, PS3:Moderate, PM4:Supporting, PP4 -
Published functional studies on red blood cells extracted from patients with hereditary elliptocytosis (HE) who harbor the c.460_462dupTTG variant, show increased spectrum dimers as compared to wild type red blood cells, suggesting the variant causes a structural defect in the spectrin molecule affecting tetramer formation (PMID: 4027386); In-frame duplication of 1 amino acid in a non-repeat region; Also known as alpha I-65 or L148dup; This variant is associated with the following publications: (PMID: 2567189, 3597773, 2794061, 1353056, 27667160, 8857939, 30393954, 31040790, 34426522, 31589614, 32623341, 34889366, 34553410, 33074480, 34201899, 37016817, 4027386) -
This variant, c.460_462dup, results in the insertion of 1 amino acid(s) of the SPTA1 protein (p.Leu155dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs757679761, gnomAD 0.09%). This variant has been observed in individuals with autosomal dominant hereditary elliptocytosis and autosomal recessive hereditary pyropoikilocytosis (PMID: 1642244, 2567189, 2794061, 3922449, 8790144, 8857939, 30393954). It has also been observed to segregate with disease in related individuals. This variant is also known as dupL154 and duplication of codon 154. ClinVar contains an entry for this variant (Variation ID: 12847). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SPTA1 function (PMID: 3922449). For these reasons, this variant has been classified as Pathogenic. -
The SPTA1 c.460_462dup, p.Leu155dup variant (rs757679761), also known as alpha(I-65), is reported in the literature multiple related and unrelated individuals and families, primarily of African descent, affected with hereditary elliptocytosis, although with variable clinical severity (del Giudice et al., 1992; Garbarz et al., 1986; Marchesi et al., 1987; Niss et al., 2016; Qualtieri et al., 1995; Roux et al., 1989; Sahr et al., 1989). This variant has also been reported in trans (on opposite chromosomes) from the alpha-LELY allele in two individuals affected with hereditary pyropoikilocytosis (Niss et al., 2016). In vitro functional analyses demonstrate impaired SPTA1 oligomer formation (Marchesi et al., 1987). This variant is reported as likely pathogenic by one laboratory in ClinVar (Variation ID: 12847). This variant is found predominantly in the African population with an overall allele frequency of 0.095% (23/24192 alleles, including no homozygotes) in the Genome Aggregation Database. This variant inserts a single leucine residue leaving the rest of the protein in-frame. Based on available information, this variant is considered to be likely pathogenic. -
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This variant, also referred to as alpha I-65, is enriched in individuals with hereditary elliptocytosis (HE) as compared to the general population (PMID: 8857939, 2567189, 30393954, 32623341). The clinical presentation of HE in individuals who have this variant in the heterozygous sate is typically characterized by mild hemolytic anemia and abnormally-shaped red blood cells. The clinical presentation is more severe when this variant is compound heterozygous with a pathogenic SPTA1 variant. This variant has also been reported to be a modifier of sickle cell anemia (PMID: 2567189, 30393954, 32623341). The frequency of this variant in the general population is uninformative but consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
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Elliptocytosis 2 Pathogenic:4
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Variant summary: SPTA1 c.460_462dupTTG (p.Leu155dup) results in an in-frame duplication that is predicted to duplicate 1 amino acid into the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 249160 control chromosomes, predominantly at a frequency of 0.0011 within the African or African-American subpopulation in the gnomAD database. c.460_462dupTTG (also described as Sp alpha[I/65] and as dupL154) has been reported in the literature in multiple heterozygous individuals, particularly of African descent, affected with hereditary elliptocytosis (e.g. Lawler_1985, Marchesi_1987, Roux_1989, Glele-Kakai_1996, Niss_2016) and in some compound heterozygous individuals affected with hereditary pyropoikilocytosis (e.g. Niss_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence revealed a decrease of the alpha l domain of spectrin and presence of an atypical peptide and also, impaired ability to undergo self association to form tetramers and higher oligomers (Lawler_1985, Marchesi_1987). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Pyropoikilocytosis, hereditary Pathogenic:1
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. Heterozygous p.L154dup has been previously reported in patients with Sp alpha I/65 hereditary elliptocytosis [PMID 2567189, 8857939] -
SPTA1-related disorder Pathogenic:1
The SPTA1 c.460_462dupTTG variant is predicted to result in an in-frame duplication (p.Leu155dup). This variant has been reported to be causative for hereditary elliptocytosis (Roux et al. 1989. PubMed ID: 2567189; Andolfo et al. 2021. PubMed ID: 34201899; Risinger et al. 2018. PubMed ID: 30393954). This variant is reported in 0.095% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at