rs35948326

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003126.4(SPTA1):c.2909C>A(p.Ala970Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0413 in 1,613,594 control chromosomes in the GnomAD database, including 1,587 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 111 hom., cov: 32)

Exomes 𝑓: 0.042 ( 1476 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:8

Conservation

PhyloP100: 5.33

Publications

25 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=0.0029602945).

BP6

Variant 1-158654738-G-T is Benign according to our data. Variant chr1-158654738-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0333 (5063/152132) while in subpopulation NFE AF = 0.0489 (3322/67974). AF 95% confidence interval is 0.0475. There are 111 homozygotes in GnomAd4. There are 2354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.2909C>A	p.Ala970Asp	missense_variant	Exon 21 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.2909C>A	p.Ala970Asp	missense_variant	Exon 21 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0333

AC:

5064

AN:

152014

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00879

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.0356

Gnomad ASJ

AF:

0.0577

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00748

Gnomad FIN

AF:

0.0386

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0489

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0330

AC:

8233

AN:

249336

AF XY:

0.0323

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0226

Gnomad ASJ exome

AF:

0.0622

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0357

Gnomad NFE exome

AF:

0.0485

Gnomad OTH exome

AF:

0.0416

GnomAD4 exome

AF:

0.0422

AC:

61624

AN:

1461462

Hom.:

1476

Cov.:

AF XY:

0.0414

AC XY:

30075

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.00615

AC:

206

AN:

33470

American (AMR)

AF:

0.0252

AC:

1126

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0600

AC:

1568

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00725

AC:

625

AN:

86258

European-Finnish (FIN)

AF:

0.0364

AC:

1934

AN:

53112

Middle Eastern (MID)

AF:

0.0199

AC:

115

AN:

5768

European-Non Finnish (NFE)

AF:

0.0483

AC:

53725

AN:

1111936

Other (OTH)

AF:

0.0385

AC:

2325

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

3231

6462

9693

12924

16155

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1978

3956

5934

7912

9890

<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:

0.0333

AC:

5063

AN:

152132

Hom.:

111

Cov.:

AF XY:

0.0317

AC XY:

2354

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00876

AC:

364

AN:

41530

American (AMR)

AF:

0.0356

AC:

543

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.0577

AC:

200

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00769

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0386

AC:

409

AN:

10600

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0489

AC:

3322

AN:

67974

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

248

497

745

994

1242

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0435

Hom.:

587

Bravo

AF:

0.0329

TwinsUK

AF:

0.0448

AC:

166

ALSPAC

AF:

0.0524

AC:

202

ESP6500AA

AF:

0.00718

AC:

ESP6500EA

AF:

0.0497

AC:

413

ExAC

AF:

0.0327

AC:

3948

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0461

EpiControl

AF:

0.0484

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency -

SPHEROCYTOSIS, TYPE 3, AUTOSOMAL RECESSIVE

Pathogenic:1

Sep 01, 1993

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hereditary spherocytosis type 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pyropoikilocytosis, hereditary;C1851741:Elliptocytosis 2;C2678338:Hereditary spherocytosis type 3

Benign:1

Jul 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pyropoikilocytosis, hereditary

Benign:1

May 28, 2019

Mendelics

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

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.45

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

0.000077

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.62

.;T

MetaRNN

Benign

0.0030

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L

PhyloP100

5.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.074

Sift

Benign

0.081

T;.

Sift4G

Uncertain

0.019

D;.

Polyphen

0.0010

B;B

Vest4

0.41

MPC

0.15

ClinPred

0.039

GERP RS

5.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

3.7

Varity_R

0.24

gMVP

0.28

Mutation Taster

=69/31

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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