rs757679761

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 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

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

SPTA1
NM_003126.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: -0.00400

Publications

7 publications found

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 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

SPTA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 12847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.460_462dupTTG	p.Leu154dup	conservative_inframe_insertion	Exon 4 of 52	ENST00000643759.2	NP_003117.2	P02549-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2 link	c.460_462dupTTG	p.Leu154dup	conservative_inframe_insertion	Exon 4 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000763

AC:

AN:

249160

AF XY:

0.0000370

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461584

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111804

Other (OTH)

AF:

0.000116

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000302

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00108

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000170

Hom.:

Bravo

AF:

0.000321

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

May 29, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Mar 29, 2023

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPTA1: PM3:Very Strong, PM1, PM2, PP1:Moderate, PS3:Moderate, PM4:Supporting, PP4 -

Jun 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 11, 2020

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Elliptocytosis 2

Pathogenic:4

Aug 01, 1992

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 13, 2023

Molecular Genetics and NGS Laboratory, Hospital Fundacion Valle Del Lili

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 28, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Pyropoikilocytosis, hereditary

Pathogenic:1

Oct 17, 2018

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 19, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.0040

Mutation Taster

=49/51

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over