NM_003126.4:c.6794T>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.6794T>C(p.Ile2265Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 1,567,036 control chromosomes in the GnomAD database, including 231,666 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20835 hom., cov: 30)

Exomes 𝑓: 0.54 ( 210831 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 2.96

Publications

39 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=5.061558E-6).

BP6

Variant 1-158614301-A-G is Benign according to our data. Variant chr1-158614301-A-G is described in ClinVar as Benign. ClinVar VariationId is 258957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.603 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.6794T>C	p.Ile2265Thr	missense_variant	Exon 49 of 52	ENST00000643759.2	NP_003117.2	P02549-1
SPTA1	XM_011509916.3 link	c.6794T>C	p.Ile2265Thr	missense_variant	Exon 50 of 53		XP_011508218.1	P02549-1
SPTA1	XM_011509917.4 link	c.6776T>C	p.Ile2259Thr	missense_variant	Exon 48 of 51		XP_011508219.1
SPTA1	XM_047428883.1 link	c.6473T>C	p.Ile2158Thr	missense_variant	Exon 49 of 52		XP_047284839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTA1	ENST00000643759.2 link	c.6794T>C	p.Ile2265Thr	missense_variant	Exon 49 of 52		NM_003126.4	ENSP00000495214.1	P02549-1
SPTA1	ENST00000481212.5 link	n.235T>C		non_coding_transcript_exon_variant	Exon 1 of 3	3
SPTA1	ENST00000498708.1 link	n.226T>C		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.520

AC:

78608

AN:

151026

Hom.:

20809

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.553

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.570

Gnomad EAS

AF:

0.621

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.552

Gnomad OTH

AF:

0.539

GnomAD2 exomes

AF:

0.537

AC:

129167

AN:

240394

AF XY:

0.534

show subpopulations

Gnomad AFR exome

AF:

0.421

Gnomad AMR exome

AF:

0.538

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.606

Gnomad FIN exome

AF:

0.635

Gnomad NFE exome

AF:

0.551

Gnomad OTH exome

AF:

0.544

GnomAD4 exome

AF:

0.541

AC:

765443

AN:

1415894

Hom.:

210831

Cov.:

AF XY:

0.538

AC XY:

379705

AN XY:

705974

show subpopulations

African (AFR)

AF:

0.421

AC:

13621

AN:

32316

American (AMR)

AF:

0.541

AC:

23141

AN:

42810

Ashkenazi Jewish (ASJ)

AF:

0.576

AC:

14715

AN:

25566

East Asian (EAS)

AF:

0.598

AC:

23551

AN:

39354

South Asian (SAS)

AF:

0.424

AC:

35616

AN:

83938

European-Finnish (FIN)

AF:

0.630

AC:

33315

AN:

52876

Middle Eastern (MID)

AF:

0.531

AC:

2964

AN:

5584

European-Non Finnish (NFE)

AF:

0.546

AC:

586471

AN:

1074734

Other (OTH)

AF:

0.546

AC:

32049

AN:

58716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

15441

30882

46323

61764

77205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16236

32472

48708

64944

81180

<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:

0.521

AC:

78681

AN:

151142

Hom.:

20835

Cov.:

AF XY:

0.526

AC XY:

38759

AN XY:

73716

show subpopulations

African (AFR)

AF:

0.423

AC:

17443

AN:

41236

American (AMR)

AF:

0.544

AC:

8280

AN:

15214

Ashkenazi Jewish (ASJ)

AF:

0.570

AC:

1976

AN:

3468

East Asian (EAS)

AF:

0.621

AC:

3185

AN:

5128

South Asian (SAS)

AF:

0.432

AC:

2076

AN:

4804

European-Finnish (FIN)

AF:

0.633

AC:

6506

AN:

10284

Middle Eastern (MID)

AF:

0.612

AC:

180

AN:

294

European-Non Finnish (NFE)

AF:

0.552

AC:

37386

AN:

67698

Other (OTH)

AF:

0.544

AC:

1147

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1883

3765

5648

7530

9413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

692

1384

2076

2768

3460

<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:

0.542

Hom.:

76470

Bravo

AF:

0.515

TwinsUK

AF:

0.543

AC:

2013

ALSPAC

AF:

0.540

AC:

2083

ESP6500AA

AF:

0.430

AC:

1554

ESP6500EA

AF:

0.541

AC:

4396

ExAC

AF:

0.538

AC:

64923

Asia WGS

AF:

0.553

AC:

1914

AN:

3462

EpiCase

AF:

0.554

EpiControl

AF:

0.550

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

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

- -

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.67

.;T

MetaRNN

Benign

0.0000051

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.95

N;N

PhyloP100

3.0

PrimateAI

Benign

0.33

REVEL

Benign

0.047

Sift4G

Benign

1.0

T;.

Polyphen

0.0

B;B

Vest4

0.057

MPC

0.031

ClinPred

0.0016

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.16

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