NM_003126.4:c.5958C>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.5958C>T(p.Pro1986Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,613,570 control chromosomes in the GnomAD database, including 74,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8710 hom., cov: 32)

Exomes 𝑓: 0.30 ( 65857 hom. )

Consequence

SPTA1
NM_003126.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.292

Publications

15 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=-0.54).

BP6

Variant 1-158623145-G-A is Benign according to our data. Variant chr1-158623145-G-A is described in ClinVar as Benign. ClinVar VariationId is 258949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.292 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.5958C>T	p.Pro1986Pro	synonymous_variant	Exon 43 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.5958C>T	p.Pro1986Pro	synonymous_variant	Exon 43 of 52		NM_003126.4	ENSP00000495214.1		P02549-1
SPTA1	ENST00000461624.1 link	n.504C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.331

AC:

50216

AN:

151750

Hom.:

8699

Cov.:

show subpopulations

Gnomad AFR

AF:

0.427

Gnomad AMI

AF:

0.227

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.392

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.304

Gnomad OTH

AF:

0.325

GnomAD2 exomes

AF:

0.290

AC:

72332

AN:

249348

AF XY:

0.293

show subpopulations

Gnomad AFR exome

AF:

0.430

Gnomad AMR exome

AF:

0.197

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.300

Gnomad NFE exome

AF:

0.301

Gnomad OTH exome

AF:

0.292

GnomAD4 exome

AF:

0.297

AC:

433639

AN:

1461702

Hom.:

65857

Cov.:

AF XY:

0.298

AC XY:

216462

AN XY:

727160

show subpopulations

African (AFR)

AF:

0.436

AC:

14584

AN:

33476

American (AMR)

AF:

0.203

AC:

9099

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.403

AC:

10522

AN:

26132

East Asian (EAS)

AF:

0.203

AC:

8056

AN:

39696

South Asian (SAS)

AF:

0.300

AC:

25905

AN:

86250

European-Finnish (FIN)

AF:

0.299

AC:

15968

AN:

53416

Middle Eastern (MID)

AF:

0.335

AC:

1934

AN:

5768

European-Non Finnish (NFE)

AF:

0.296

AC:

329425

AN:

1111854

Other (OTH)

AF:

0.300

AC:

18146

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

19184

38367

57551

76734

95918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10866

21732

32598

43464

54330

<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:

0.331

AC:

50268

AN:

151868

Hom.:

8710

Cov.:

AF XY:

0.331

AC XY:

24583

AN XY:

74210

show subpopulations

African (AFR)

AF:

0.427

AC:

17673

AN:

41394

American (AMR)

AF:

0.255

AC:

3893

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.392

AC:

1361

AN:

3470

East Asian (EAS)

AF:

0.185

AC:

949

AN:

5140

South Asian (SAS)

AF:

0.290

AC:

1393

AN:

4798

European-Finnish (FIN)

AF:

0.317

AC:

3343

AN:

10538

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.304

AC:

20642

AN:

67954

Other (OTH)

AF:

0.327

AC:

688

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1647

3294

4941

6588

8235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<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:

0.310

Hom.:

5085

Bravo

AF:

0.329

Asia WGS

AF:

0.245

AC:

852

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

- -

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

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.56

(source)

DANN

Benign

0.48

PhyloP100

-0.29

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