chr1-158642446-A-G

Variant names:

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.4702T>C(p.Cys1568Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 1,613,184 control chromosomes in the GnomAD database, including 264,753 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. C1568H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.60 ( 27944 hom., cov: 31)

Exomes 𝑓: 0.57 ( 236809 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.976

Publications

36 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.015965E-6).

BP6

Variant 1-158642446-A-G is Benign according to our data. Variant chr1-158642446-A-G is described in ClinVar as Benign. ClinVar VariationId is 258942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

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.4702T>C	p.Cys1568Arg	missense	Exon 33 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.4702T>C	p.Cys1568Arg	missense	Exon 33 of 52	ENSP00000495214.1	P02549-1
	SPTA1	ENST00000465741.1	TSL:3	n.87T>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.603

AC:

91602

AN:

151878

Hom.:

27885

Cov.:

show subpopulations

Gnomad AFR

AF:

0.665

Gnomad AMI

AF:

0.554

Gnomad AMR

AF:

0.582

Gnomad ASJ

AF:

0.631

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.647

Gnomad MID

AF:

0.687

Gnomad NFE

AF:

0.569

Gnomad OTH

AF:

0.606

GnomAD2 exomes

AF:

0.578

AC:

143919

AN:

248976

AF XY:

0.573

show subpopulations

Gnomad AFR exome

AF:

0.666

Gnomad AMR exome

AF:

0.565

Gnomad ASJ exome

AF:

0.640

Gnomad EAS exome

AF:

0.616

Gnomad FIN exome

AF:

0.643

Gnomad NFE exome

AF:

0.572

Gnomad OTH exome

AF:

0.581

GnomAD4 exome

AF:

0.568

AC:

829521

AN:

1461188

Hom.:

236809

Cov.:

AF XY:

0.565

AC XY:

410767

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.676

AC:

22616

AN:

33440

American (AMR)

AF:

0.568

AC:

25368

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.639

AC:

16691

AN:

26112

East Asian (EAS)

AF:

0.607

AC:

24094

AN:

39676

South Asian (SAS)

AF:

0.483

AC:

41668

AN:

86242

European-Finnish (FIN)

AF:

0.640

AC:

34149

AN:

53398

Middle Eastern (MID)

AF:

0.628

AC:

3616

AN:

5760

European-Non Finnish (NFE)

AF:

0.563

AC:

625985

AN:

1111540

Other (OTH)

AF:

0.586

AC:

35334

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

20727

41454

62182

82909

103636

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17486

34972

52458

69944

87430

<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:

0.603

AC:

91719

AN:

151996

Hom.:

27944

Cov.:

AF XY:

0.607

AC XY:

45118

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.666

AC:

27590

AN:

41446

American (AMR)

AF:

0.582

AC:

8891

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

2190

AN:

3470

East Asian (EAS)

AF:

0.632

AC:

3259

AN:

5154

South Asian (SAS)

AF:

0.478

AC:

2302

AN:

4812

European-Finnish (FIN)

AF:

0.647

AC:

6844

AN:

10570

Middle Eastern (MID)

AF:

0.687

AC:

202

AN:

294

European-Non Finnish (NFE)

AF:

0.569

AC:

38650

AN:

67950

Other (OTH)

AF:

0.609

AC:

1288

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1847

3694

5540

7387

9234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<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:

0.583

Hom.:

60460

Bravo

AF:

0.605

TwinsUK

AF:

0.557

AC:

2065

ALSPAC

AF:

0.557

AC:

2148

ESP6500AA

AF:

0.678

AC:

2688

ESP6500EA

AF:

0.562

AC:

4689

ExAC

AF:

0.579

AC:

69915

Asia WGS

AF:

0.599

AC:

2080

AN:

3476

EpiCase

AF:

0.575

EpiControl

AF:

0.574

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (3)

Elliptocytosis 2 (2)

Hereditary spherocytosis type 3 (2)

Pyropoikilocytosis, hereditary (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.036

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.8

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.17

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.40

MetaRNN

Benign

0.0000040

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.8

PhyloP100

0.98

PrimateAI

Benign

0.27

PROVEAN

Benign

4.1

REVEL

Benign

0.049

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.071

MPC

0.038

ClinPred

0.0043

GERP RS

1.0

Varity_R

0.13

gMVP

0.090

Mutation Taster

=100/0

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