rs41273523

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003126.4(SPTA1):c.4490G>A(p.Gly1497Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0157 in 1,613,718 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.016 ( 211 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: 4.75

Publications

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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053780377).

BP6

Variant 1-158642929-C-T is Benign according to our data. Variant chr1-158642929-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258940.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1959/152178) while in subpopulation NFE AF = 0.0189 (1285/67998). AF 95% confidence interval is 0.018. There are 19 homozygotes in GnomAd4. There are 985 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AD,AR gene

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.4490G>A	p.Gly1497Glu	missense	Exon 32 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.4490G>A	p.Gly1497Glu	missense	Exon 32 of 52	ENSP00000495214.1	P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1958

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00793

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00187

Gnomad FIN

AF:

0.0337

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0189

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0140

AC:

3496

AN:

249130

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00723

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0318

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0170

GnomAD4 exome

AF:

0.0160

AC:

23330

AN:

1461540

Hom.:

211

Cov.:

AF XY:

0.0157

AC XY:

11412

AN XY:

727070

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

33452

American (AMR)

AF:

0.00707

AC:

316

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

384

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00319

AC:

275

AN:

86254

European-Finnish (FIN)

AF:

0.0303

AC:

1619

AN:

53410

Middle Eastern (MID)

AF:

0.00625

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.0178

AC:

19789

AN:

1111810

Other (OTH)

AF:

0.0139

AC:

842

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1513

3027

4540

6054

7567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0129

AC:

1959

AN:

152178

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

985

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.00299

AC:

124

AN:

41530

American (AMR)

AF:

0.00792

AC:

121

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00922

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0337

AC:

357

AN:

10596

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0189

AC:

1285

AN:

67998

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0165

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00376

AC:

ESP6500EA

AF:

0.0170

AC:

142

ExAC

AF:

0.0145

AC:

1756

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0206

EpiControl

AF:

0.0180

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

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

Benign

0.18

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.1

PhyloP100

4.8

PrimateAI

Benign

0.47

PROVEAN

Pathogenic

-5.8

REVEL

Benign

0.14

Sift

Benign

0.064

Sift4G

Benign

0.26

Polyphen

0.35

Vest4

0.23

MPC

0.075

ClinPred

0.075

GERP RS

0.0036

Varity_R

0.34

gMVP

0.14

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over