1-158661316-G-C

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.2558C>G(p.Thr853Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0171 in 1,613,640 control chromosomes in the GnomAD database, including 3,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 1943 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 1774 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.77

Publications

12 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=0.0017263591).

BP6

Variant 1-158661316-G-C is Benign according to our data. Variant chr1-158661316-G-C is described in ClinVar as Benign. ClinVar VariationId is 258923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.2558C>G	p.Thr853Arg	missense_variant	Exon 18 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.2558C>G	p.Thr853Arg	missense_variant	Exon 18 of 52		NM_003126.4	ENSP00000495214.1		P02549-1
SPTA1	ENST00000647256.1 link	n.158C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.0877

AC:

13327

AN:

151876

Hom.:

1938

Cov.:

show subpopulations

Gnomad AFR

AF:

0.303

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0346

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00125

Gnomad OTH

AF:

0.0635

GnomAD2 exomes

AF:

0.0234

AC:

5837

AN:

249420

AF XY:

0.0182

show subpopulations

Gnomad AFR exome

AF:

0.312

Gnomad AMR exome

AF:

0.0163

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00149

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.00975

AC:

14253

AN:

1461646

Hom.:

1774

Cov.:

AF XY:

0.00852

AC XY:

6196

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.313

AC:

10480

AN:

33432

American (AMR)

AF:

0.0185

AC:

829

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

419

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00106

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0374

AC:

216

AN:

5768

European-Non Finnish (NFE)

AF:

0.000775

AC:

862

AN:

1111878

Other (OTH)

AF:

0.0223

AC:

1346

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

664

1327

1991

2654

3318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.0878

AC:

13351

AN:

151994

Hom.:

1943

Cov.:

AF XY:

0.0854

AC XY:

6347

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.302

AC:

12526

AN:

41424

American (AMR)

AF:

0.0346

AC:

529

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00312

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00125

AC:

AN:

67988

Other (OTH)

AF:

0.0628

AC:

132

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

489

978

1468

1957

2446

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0148

Hom.:

195

Bravo

AF:

0.0992

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.289

AC:

1121

ESP6500EA

AF:

0.00253

AC:

ExAC

AF:

0.0282

AC:

3410

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 03, 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

- -

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

0.15

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

T;T

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.75

.;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PhyloP100

5.8

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.8

D;.

REVEL

Benign

0.19

Sift

Benign

0.26

T;.

Sift4G

Benign

0.065

T;.

Polyphen

0.84

P;P

Vest4

0.53

MPC

0.22

ClinPred

0.033

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.33

Mutation Taster

=79/21

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