chr1-158638145-T-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.5077A>C(p.Lys1693Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,752 control chromosomes in the GnomAD database, including 59,409 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 (★★).

Frequency

Genomes: 𝑓 0.24 ( 4874 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54535 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0140

Publications

47 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=4.7916174E-4).

BP6

Variant 1-158638145-T-G is Benign according to our data. Variant chr1-158638145-T-G is described in ClinVar as Benign. ClinVar VariationId is 258943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.5077A>C	p.Lys1693Gln	missense_variant	Exon 36 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.5077A>C	p.Lys1693Gln	missense_variant	Exon 36 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.239

AC:

36294

AN:

152018

Hom.:

4864

Cov.:

show subpopulations

Gnomad AFR

AF:

0.121

Gnomad AMI

AF:

0.325

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.236

Gnomad EAS

AF:

0.452

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.329

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.259

GnomAD2 exomes

AF:

0.280

AC:

69723

AN:

249014

AF XY:

0.275

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.237

Gnomad EAS exome

AF:

0.434

Gnomad FIN exome

AF:

0.344

Gnomad NFE exome

AF:

0.271

Gnomad OTH exome

AF:

0.285

GnomAD4 exome

AF:

0.268

AC:

391943

AN:

1461616

Hom.:

54535

Cov.:

AF XY:

0.265

AC XY:

192648

AN XY:

727114

show subpopulations

African (AFR)

AF:

0.119

AC:

3978

AN:

33472

American (AMR)

AF:

0.359

AC:

16023

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.235

AC:

6135

AN:

26130

East Asian (EAS)

AF:

0.408

AC:

16198

AN:

39692

South Asian (SAS)

AF:

0.182

AC:

15705

AN:

86258

European-Finnish (FIN)

AF:

0.340

AC:

18161

AN:

53350

Middle Eastern (MID)

AF:

0.280

AC:

1615

AN:

5766

European-Non Finnish (NFE)

AF:

0.268

AC:

297441

AN:

1111894

Other (OTH)

AF:

0.276

AC:

16687

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

18516

37032

55547

74063

92579

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9938

19876

29814

39752

49690

<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:

0.239

AC:

36344

AN:

152136

Hom.:

4874

Cov.:

AF XY:

0.243

AC XY:

18101

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.121

AC:

5038

AN:

41522

American (AMR)

AF:

0.316

AC:

4833

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.236

AC:

819

AN:

3472

East Asian (EAS)

AF:

0.452

AC:

2329

AN:

5154

South Asian (SAS)

AF:

0.186

AC:

896

AN:

4820

European-Finnish (FIN)

AF:

0.329

AC:

3488

AN:

10588

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.265

AC:

18012

AN:

67986

Other (OTH)

AF:

0.261

AC:

551

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1375

2750

4124

5499

6874

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

382

764

1146

1528

1910

<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:

0.259

Hom.:

19196

Bravo

AF:

0.238

TwinsUK

AF:

0.268

AC:

995

ALSPAC

AF:

0.260

AC:

1002

ESP6500AA

AF:

0.123

AC:

467

ESP6500EA

AF:

0.262

AC:

2159

ExAC

AF:

0.273

AC:

33025

Asia WGS

AF:

0.347

AC:

1202

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Elliptocytosis 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary spherocytosis type 3

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pyropoikilocytosis, hereditary

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

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

0.075

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.034

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.45

.;T

MetaRNN

Benign

0.00048

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;N

PhyloP100

-0.014

PrimateAI

Benign

0.26

PROVEAN

Benign

0.74

N;.

REVEL

Benign

0.013

Sift

Benign

0.26

T;.

Sift4G

Uncertain

0.048

D;.

Polyphen

0.0

B;B

Vest4

0.053

MPC

0.029

ClinPred

0.0070

GERP RS

-5.4

Varity_R

0.28

gMVP

0.061

Mutation Taster

=94/6

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over