rs78394850

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.6046C>T(p.Arg2016Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0241 in 1,613,990 control chromosomes in the GnomAD database, including 1,324 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2016H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.054 ( 487 hom., cov: 33)

Exomes 𝑓: 0.021 ( 837 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.54

Publications

9 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=0.0038462281).

BP6

Variant 1-158623057-G-A is Benign according to our data. Variant chr1-158623057-G-A is described in ClinVar as Benign. ClinVar VariationId is 258951.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.6046C>T	p.Arg2016Cys	missense_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.6046C>T	p.Arg2016Cys	missense_variant	Exon 43 of 52		NM_003126.4	ENSP00000495214.1		P02549-1
SPTA1	ENST00000461624.1 link	n.592C>T		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0534

AC:

8125

AN:

152048

Hom.:

485

Cov.:

show subpopulations

Gnomad AFR

AF:

0.145

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0271

Gnomad ASJ

AF:

0.0496

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0460

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0483

GnomAD2 exomes

AF:

0.0295

AC:

7359

AN:

249486

AF XY:

0.0294

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.0200

Gnomad ASJ exome

AF:

0.0517

Gnomad EAS exome

AF:

0.000278

Gnomad FIN exome

AF:

0.00840

Gnomad NFE exome

AF:

0.0178

Gnomad OTH exome

AF:

0.0301

GnomAD4 exome

AF:

0.0211

AC:

30772

AN:

1461824

Hom.:

837

Cov.:

AF XY:

0.0218

AC XY:

15833

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.147

AC:

4914

AN:

33472

American (AMR)

AF:

0.0210

AC:

941

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0529

AC:

1382

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0539

AC:

4649

AN:

86252

European-Finnish (FIN)

AF:

0.00957

AC:

511

AN:

53418

Middle Eastern (MID)

AF:

0.0855

AC:

493

AN:

5768

European-Non Finnish (NFE)

AF:

0.0144

AC:

16067

AN:

1111966

Other (OTH)

AF:

0.0300

AC:

1813

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

1850

3700

5549

7399

9249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

704

1408

2112

2816

3520

<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:

0.0536

AC:

8157

AN:

152166

Hom.:

487

Cov.:

AF XY:

0.0530

AC XY:

3942

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.146

AC:

6041

AN:

41486

American (AMR)

AF:

0.0271

AC:

414

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0496

AC:

172

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.0459

AC:

221

AN:

4818

European-Finnish (FIN)

AF:

0.00952

AC:

101

AN:

10614

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0159

AC:

1083

AN:

68008

Other (OTH)

AF:

0.0478

AC:

101

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

364

727

1091

1454

1818

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:

0.0273

Hom.:

542

Bravo

AF:

0.0587

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.140

AC:

541

ESP6500EA

AF:

0.0158

AC:

131

ExAC

AF:

0.0321

AC:

3874

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

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) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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. -

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

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

.;D

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

9.5

PrimateAI

Benign

0.31

REVEL

Uncertain

0.34

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.68

MPC

0.24

ClinPred

0.017

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.43

Mutation Taster

=59/41

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