1-158656588-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003126.4(SPTA1):c.2874G>A(p.Leu958Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 1,612,524 control chromosomes in the GnomAD database, including 73,055 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 14880 hom., cov: 32)

Exomes 𝑓: 0.27 ( 58175 hom. )

Consequence

SPTA1
NM_003126.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.754

Publications

33 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 1-158656588-C-T is Benign according to our data. Variant chr1-158656588-C-T is described in ClinVar as Benign. ClinVar VariationId is 258926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.754 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.2874G>A	p.Leu958Leu	synonymous_variant	Exon 20 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.2874G>A	p.Leu958Leu	synonymous_variant	Exon 20 of 52		NM_003126.4	ENSP00000495214.1
SPTA1	ENST00000647256.1 link	n.*43G>A		downstream_gene_variant

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59904

AN:

151940

Hom.:

14839

Cov.:

show subpopulations

Gnomad AFR

AF:

0.706

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.435

Gnomad SAS

AF:

0.167

Gnomad FIN

AF:

0.320

Gnomad MID

AF:

0.293

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.359

GnomAD2 exomes

AF:

0.307

AC:

76446

AN:

249068

AF XY:

0.290

show subpopulations

Gnomad AFR exome

AF:

0.721

Gnomad AMR exome

AF:

0.372

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.254

Gnomad OTH exome

AF:

0.287

GnomAD4 exome

AF:

0.268

AC:

391598

AN:

1460466

Hom.:

58175

Cov.:

AF XY:

0.262

AC XY:

190323

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.722

AC:

24119

AN:

33416

American (AMR)

AF:

0.370

AC:

16547

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

6171

AN:

26116

East Asian (EAS)

AF:

0.381

AC:

15083

AN:

39634

South Asian (SAS)

AF:

0.160

AC:

13785

AN:

86226

European-Finnish (FIN)

AF:

0.332

AC:

17656

AN:

53242

Middle Eastern (MID)

AF:

0.279

AC:

1610

AN:

5762

European-Non Finnish (NFE)

AF:

0.251

AC:

278545

AN:

1111048

Other (OTH)

AF:

0.300

AC:

18082

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

13839

27677

41516

55354

69193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9618

19236

28854

38472

48090

<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:

0.395

AC:

60010

AN:

152058

Hom.:

14880

Cov.:

AF XY:

0.394

AC XY:

29265

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.706

AC:

29284

AN:

41480

American (AMR)

AF:

0.353

AC:

5389

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

846

AN:

3468

East Asian (EAS)

AF:

0.435

AC:

2245

AN:

5162

South Asian (SAS)

AF:

0.167

AC:

805

AN:

4818

European-Finnish (FIN)

AF:

0.320

AC:

3389

AN:

10580

Middle Eastern (MID)

AF:

0.291

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.249

AC:

16931

AN:

67968

Other (OTH)

AF:

0.361

AC:

763

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1577

3154

4731

6308

7885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

516

1032

1548

2064

2580

<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:

0.291

Hom.:

34626

Bravo

AF:

0.416

Asia WGS

AF:

0.358

AC:

1242

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 24, 2021

GeneDx

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

- -

not specified

Benign:3

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.084

(source)

DANN

Benign

0.43

PhyloP100

-0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

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