1-158627717-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003126.4(SPTA1):c.5572C>G(p.Leu1858Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,609,240 control chromosomes in the GnomAD database, including 60,931 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.25 ( 5114 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55817 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:15

Conservation

PhyloP100: 2.72

Publications

48 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018082857).

BP6

Variant 1-158627717-G-C is Benign according to our data. Variant chr1-158627717-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258948.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.5572C>G	p.Leu1858Val	missense	Exon 40 of 52	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.5572C>G	p.Leu1858Val	missense	Exon 40 of 52	ENSP00000495214.1
	SPTA1	ENST00000461624.1	TSL:2	n.118C>G		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38547

AN:

151894

Hom.:

5113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.198

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.218

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.244

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.321

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.259

GnomAD2 exomes

AF:

0.255

AC:

63178

AN:

248208

AF XY:

0.259

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.350

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.261

GnomAD4 exome

AF:

0.273

AC:

397913

AN:

1457228

Hom.:

55817

Cov.:

AF XY:

0.274

AC XY:

198451

AN XY:

725124

show subpopulations

African (AFR)

AF:

0.198

AC:

6628

AN:

33422

American (AMR)

AF:

0.176

AC:

7866

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.351

AC:

9151

AN:

26102

East Asian (EAS)

AF:

0.203

AC:

8041

AN:

39652

South Asian (SAS)

AF:

0.246

AC:

21211

AN:

86218

European-Finnish (FIN)

AF:

0.289

AC:

14966

AN:

51722

Middle Eastern (MID)

AF:

0.243

AC:

1402

AN:

5762

European-Non Finnish (NFE)

AF:

0.282

AC:

312693

AN:

1109394

Other (OTH)

AF:

0.265

AC:

15955

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

13819

27638

41457

55276

69095

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10264

20528

30792

41056

51320

<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:

0.254

AC:

38556

AN:

152012

Hom.:

5114

Cov.:

AF XY:

0.255

AC XY:

18949

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.198

AC:

8211

AN:

41452

American (AMR)

AF:

0.218

AC:

3321

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.343

AC:

1188

AN:

3464

East Asian (EAS)

AF:

0.185

AC:

956

AN:

5166

South Asian (SAS)

AF:

0.244

AC:

1176

AN:

4816

European-Finnish (FIN)

AF:

0.309

AC:

3260

AN:

10562

Middle Eastern (MID)

AF:

0.321

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.288

AC:

19589

AN:

67976

Other (OTH)

AF:

0.262

AC:

554

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1445

2889

4334

5778

7223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<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:

0.283

Hom.:

1175

Bravo

AF:

0.242

TwinsUK

AF:

0.276

AC:

1024

ALSPAC

AF:

0.284

AC:

1093

ESP6500AA

AF:

0.192

AC:

710

ESP6500EA

AF:

0.276

AC:

2255

ExAC

AF:

0.256

AC:

30969

Asia WGS

AF:

0.209

AC:

729

AN:

3478

EpiCase

AF:

0.283

EpiControl

AF:

0.280

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 28, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Commonly referred to as the AlphaLELY allele when is cis with c.6531-12C>T, a low expression allele that results in partial skipping of exon 46 and expression of hereditary elliptocytosis when in trans with a pathogenic SPTA1 variant (Wilmotte et al., 1999); Observed with c.6531-12C>T multiple times with a variant on the opposite allele (in trans) in unrelated patients with hereditary pyropoikilocytosis or hereditary elliptocytosis in the published literature; is reported to result in more severe disease when in trans with a pathogenic variant (Niss et al., 2016; Ma et al., 2018; Aggarwal et al., 2020); This variant is associated with the following publications: (PMID: 32287101, 32581362, 31602632, 10192450)

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 15, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Elliptocytosis 2

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spherocytosis type 3

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pyropoikilocytosis, hereditary

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hemolytic anemia

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Pyropoikilocytosis, hereditary;C1851741:Elliptocytosis 2;C2678338:Hereditary spherocytosis type 3

Benign:1

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

Intellectual developmental disorder, X-linked 111

Benign:1

Sep 24, 2024

Johns Hopkins Genomics, Johns Hopkins University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.5572C>G in SPTA1 (rs3737515) reaches polymorphic frequency (>1%) in a large population dataset (gnomAD v4.1.0: 436469/1609240 alleles; 27.1%, 60931 homozygotes) and has been reported in ClinVar (Variation ID 258948). Based on this population frequency alone, c.5572C>G is considered to be benign. c.5572C>G is known to co-occur with c.6531-12C>T on the same chromosome copy, and this complex allele is called the alpha LELY allele. Alpha LELY has been shown to result in partial skipping of exon 466 and has been reported in trans with a pathogenic or likely pathogenic SPTA1 variant in multiple patients with hereditary elliptocytosis and pyropoikilocytosis. Therefore, while we consider alpha LELY to be benign in the heterozygous state, its role as a modifier of SPTA1-related disorders when occurring in the compound heterozygous state with a pathogenic or likely pathogenic SPTA1 variant is not ruled out.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.10

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

PhyloP100

2.7

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.18

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.019

Polyphen

0.60

Vest4

0.24

MPC

0.15

ClinPred

0.027

GERP RS

2.7

Varity_R

0.47

gMVP

0.10

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over