rs148912436

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BS1BS2_Supporting

The NM_003126.4(SPTA1):c.1958A>G(p.Tyr653Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 1,614,078 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y653H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0080 ( 2 hom., cov: 32)

Exomes 𝑓: 0.010 ( 88 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 7.39

Publications

14 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, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
elliptocytosis 2
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
pyropoikilocytosis, hereditary
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, 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

new If you want to explore the variant's impact on the transcript NM_003126.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012779087).

BP6

Variant 1-158667938-T-C is Benign according to our data. Variant chr1-158667938-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258918.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00802 (1221/152278) while in subpopulation NFE AF = 0.0117 (796/68010). AF 95% confidence interval is 0.011. There are 2 homozygotes in GnomAd4. There are 579 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003126.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	NM_003126.4	MANE Select	c.1958A>G	p.Tyr653Cys	missense	Exon 15 of 52	NP_003117.2	P02549-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTA1	ENST00000643759.2	MANE Select	c.1958A>G	p.Tyr653Cys	missense	Exon 15 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.00804

AC:

1223

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00244

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00649

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.00814

AC:

2030

AN:

249402

AF XY:

0.00804

show subpopulations

Gnomad AFR exome

AF:

0.00245

Gnomad AMR exome

AF:

0.00759

Gnomad ASJ exome

AF:

0.00854

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00728

Gnomad NFE exome

AF:

0.0118

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0102

AC:

14843

AN:

1461800

Hom.:

Cov.:

AF XY:

0.00987

AC XY:

7175

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

33470

American (AMR)

AF:

0.00731

AC:

327

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39686

South Asian (SAS)

AF:

0.00308

AC:

266

AN:

86258

European-Finnish (FIN)

AF:

0.00867

AC:

463

AN:

53402

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0115

AC:

12791

AN:

1111980

Other (OTH)

AF:

0.0105

AC:

637

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

905

1810

2716

3621

4526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.00802

AC:

1221

AN:

152278

Hom.:

Cov.:

AF XY:

0.00778

AC XY:

579

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00243

AC:

101

AN:

41564

American (AMR)

AF:

0.0113

AC:

173

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00270

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00649

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

796

AN:

68010

Other (OTH)

AF:

0.0118

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.0103

Hom.:

Bravo

AF:

0.00810

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0120

EpiControl

AF:

0.0141

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (2)

Elliptocytosis 2 (1)

Hereditary spherocytosis type 3 (1)

Pyropoikilocytosis, hereditary (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

PhyloP100

7.4

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.34

Sift

Benign

0.070

Sift4G

Pathogenic

0.0010

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.29

Mutation Taster

=80/20

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over