rs757679761

chr1-158681595-G-GCAA

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM4_Supporting PP5_Very_Strong

The NM_003126.4(SPTA1):c.462_463insTTG(p.Leu155dup) variant causes a 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:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: SPTA1 NM_003126.4 inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: -0.00400

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003126.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-158681595-G-GCAA is Pathogenic according to our data. Variant chr1-158681595-G-GCAA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTA1	NM_003126.4	c.462_463insTTG	p.Leu155dup	inframe_insertion	4/52	ENST00000643759.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTA1	ENST00000643759.2	c.462_463insTTG	p.Leu155dup	inframe_insertion	4/52		NM_003126.4	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00109

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: 0.000479

GnomAD3 exomes AF: 0.0000763 AC: 19 AN: 249160 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135152

Gnomad AFR exome AF: 0.00110

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: 0.00000885

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000342 AC: 50 AN: 1461584 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727096

Gnomad4 AFR exome AF: 0.00114

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: 0.00000270

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74438

Gnomad4 AFR AF: 0.00108

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: 0.000474

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000321

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 29, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SPTA1: PM3:Very Strong, PM1, PM2, PP1:Moderate, PS3:Moderate, PM4:Supporting, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	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 protein 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2023	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 (Lawler et al., 1985); 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, 4027386) -

Elliptocytosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili	Nov 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1992	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -

Pyropoikilocytosis, hereditary Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 17, 2018

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] -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757679761; hg19: chr1-158651385;