1-158662741-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000643759.2(SPTA1):c.2425A>G(p.Ile809Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,840 control chromosomes in the GnomAD database, including 3,506 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.085 ( 1830 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 1676 hom. )

Consequence

SPTA1
ENST00000643759.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.58

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017371178).

BP6

Variant 1-158662741-T-C is Benign according to our data. Variant chr1-158662741-T-C is described in ClinVar as Benign. ClinVar VariationId is 258921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000643759.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.2425A>G	p.Ile809Val	missense	Exon 17 of 52	NP_003117.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.2425A>G	p.Ile809Val	missense	Exon 17 of 52	ENSP00000495214.1

Frequencies

GnomAD3 genomes

AF:

0.0849

AC:

12900

AN:

151994

Hom.:

1825

Cov.:

show subpopulations

Gnomad AFR

AF:

0.293

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0342

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.0590

GnomAD2 exomes

AF:

0.0227

AC:

5671

AN:

249446

AF XY:

0.0177

show subpopulations

Gnomad AFR exome

AF:

0.303

Gnomad AMR exome

AF:

0.0159

Gnomad ASJ exome

AF:

0.0168

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.00953

AC:

13924

AN:

1461726

Hom.:

1676

Cov.:

AF XY:

0.00831

AC XY:

6044

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.305

AC:

10200

AN:

33448

American (AMR)

AF:

0.0182

AC:

815

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0161

AC:

420

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.00101

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0375

AC:

215

AN:

5730

European-Non Finnish (NFE)

AF:

0.000769

AC:

855

AN:

1111956

Other (OTH)

AF:

0.0219

AC:

1321

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

646

1292

1939

2585

3231

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

306

612

918

1224

1530

<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:

0.0850

AC:

12924

AN:

152114

Hom.:

1830

Cov.:

AF XY:

0.0828

AC XY:

6162

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.293

AC:

12119

AN:

41408

American (AMR)

AF:

0.0341

AC:

522

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00290

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

68014

Other (OTH)

AF:

0.0583

AC:

123

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

462

924

1385

1847

2309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0251

Hom.:

1109

Bravo

AF:

0.0961

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.278

AC:

1083

ESP6500EA

AF:

0.00230

AC:

ExAC

AF:

0.0273

AC:

3297

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.00147

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Elliptocytosis 2 (1)

Hereditary spherocytosis type 3 (1)

not specified (1)

Pyropoikilocytosis, hereditary (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

PhyloP100

7.6

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.91

REVEL

Benign

0.23

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.35

MPC

0.21

ClinPred

0.036

GERP RS

4.3

Varity_R

0.41

gMVP

0.10

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over