1-158623111-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003126.4(SPTA1):c.5992G>C(p.Ala1998Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0235 in 1,613,978 control chromosomes in the GnomAD database, including 1,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.053 ( 491 hom., cov: 32)

Exomes 𝑓: 0.020 ( 819 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.79

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0021986663).

BP6

Variant 1-158623111-C-G is Benign according to our data. Variant chr1-158623111-C-G is described in ClinVar as Benign. ClinVar VariationId is 258950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.5992G>C	p.Ala1998Pro	missense_variant	Exon 43 of 52	ENST00000643759.2	NP_003117.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2 link	c.5992G>C	p.Ala1998Pro	missense_variant	Exon 43 of 52		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000461624.1 link	n.538G>C		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0531

AC:

8078

AN:

152102

Hom.:

489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0268

Gnomad ASJ

AF:

0.0495

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0456

Gnomad FIN

AF:

0.00885

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0479

GnomAD2 exomes

AF:

0.0292

AC:

7273

AN:

249460

AF XY:

0.0291

show subpopulations

Gnomad AFR exome

AF:

0.145

Gnomad AMR exome

AF:

0.0198

Gnomad ASJ exome

AF:

0.0518

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00812

Gnomad NFE exome

AF:

0.0171

Gnomad OTH exome

AF:

0.0297

GnomAD4 exome

AF:

0.0204

AC:

29881

AN:

1461758

Hom.:

819

Cov.:

AF XY:

0.0212

AC XY:

15442

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.147

AC:

4907

AN:

33464

American (AMR)

AF:

0.0209

AC:

933

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0528

AC:

1380

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0539

AC:

4646

AN:

86254

European-Finnish (FIN)

AF:

0.00929

AC:

496

AN:

53418

Middle Eastern (MID)

AF:

0.0855

AC:

493

AN:

5764

European-Non Finnish (NFE)

AF:

0.0137

AC:

15255

AN:

1111914

Other (OTH)

AF:

0.0293

AC:

1769

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.423

Heterozygous variant carriers

1803

3606

5410

7213

9016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

672

1344

2016

2688

3360

<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:

0.0533

AC:

8110

AN:

152220

Hom.:

491

Cov.:

AF XY:

0.0526

AC XY:

3915

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.146

AC:

6050

AN:

41516

American (AMR)

AF:

0.0267

AC:

409

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0495

AC:

172

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.0455

AC:

219

AN:

4816

European-Finnish (FIN)

AF:

0.00885

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0153

AC:

1042

AN:

68028

Other (OTH)

AF:

0.0474

AC:

100

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

377

755

1132

1510

1887

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

264

352

440

<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:

0.0185

Hom.:

Bravo

AF:

0.0585

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.141

AC:

550

ESP6500EA

AF:

0.0152

AC:

126

ExAC

AF:

0.0317

AC:

3833

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Feb 04, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 24193021)

Elliptocytosis 2

Benign:1

Jan 13, 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.

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary spherocytosis type 3

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pyropoikilocytosis, hereditary

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.0

.;T

MetaRNN

Benign

0.0022

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.8

M;M

PhyloP100

3.8

PrimateAI

Benign

0.38

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.25

Sift

Pathogenic

0.0

.;.

Sift4G

Uncertain

0.0040

D;.

Vest4

0.47

ClinPred

0.017

GERP RS

3.9

Varity_R

0.77

gMVP

0.40

Mutation Taster

=92/8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over