rs34973695

Variant names:

Variant summary

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

The NM_003126.4(SPTA1):c.4453C>T(p.Leu1485Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0233 in 1,613,524 control chromosomes in the GnomAD database, including 524 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 39 hom., cov: 32)

Exomes 𝑓: 0.024 ( 485 hom. )

Consequence

SPTA1
NM_003126.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 4.61

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
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009739518).

BP6

Variant 1-158642966-G-A is Benign according to our data. Variant chr1-158642966-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 258938.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0176 (2677/152166) while in subpopulation SAS AF = 0.0281 (135/4806). AF 95% confidence interval is 0.0258. There are 39 homozygotes in GnomAd4. There are 1271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 39 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTA1	NM_003126.4 link	c.4453C>T	p.Leu1485Phe	missense_variant	Exon 32 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.4453C>T	p.Leu1485Phe	missense_variant	Exon 32 of 52		NM_003126.4	ENSP00000495214.1		P02549-1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2674

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00435

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.0274

Gnomad FIN

AF:

0.0126

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.0268

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.0198

AC:

4933

AN:

248812

AF XY:

0.0212

show subpopulations

Gnomad AFR exome

AF:

0.00484

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.000167

Gnomad FIN exome

AF:

0.0127

Gnomad NFE exome

AF:

0.0252

Gnomad OTH exome

AF:

0.0204

GnomAD4 exome

AF:

0.0239

AC:

34963

AN:

1461358

Hom.:

485

Cov.:

AF XY:

0.0243

AC XY:

17630

AN XY:

726964

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

33452

American (AMR)

AF:

0.0142

AC:

634

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.0340

AC:

887

AN:

26122

East Asian (EAS)

AF:

0.000101

AC:

AN:

39686

South Asian (SAS)

AF:

0.0280

AC:

2411

AN:

86244

European-Finnish (FIN)

AF:

0.0128

AC:

684

AN:

53392

Middle Eastern (MID)

AF:

0.00938

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0260

AC:

28870

AN:

1111696

Other (OTH)

AF:

0.0219

AC:

1322

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

2172

4344

6517

8689

10861

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1086

2172

3258

4344

5430

<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:

0.0176

AC:

2677

AN:

152166

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1271

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00433

AC:

180

AN:

41548

American (AMR)

AF:

0.0145

AC:

221

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

141

AN:

3472

East Asian (EAS)

AF:

0.000966

AC:

AN:

5176

South Asian (SAS)

AF:

0.0281

AC:

135

AN:

4806

European-Finnish (FIN)

AF:

0.0126

AC:

133

AN:

10580

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0268

AC:

1821

AN:

67990

Other (OTH)

AF:

0.0156

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

136

271

407

542

678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0238

Hom.:

158

Bravo

AF:

0.0173

TwinsUK

AF:

0.0235

AC:

ALSPAC

AF:

0.0249

AC:

ESP6500AA

AF:

0.00476

AC:

ESP6500EA

AF:

0.0247

AC:

206

ExAC

AF:

0.0194

AC:

2347

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.0266

EpiControl

AF:

0.0272

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 08, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2 -

Hereditary spherocytosis type 3

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Pyropoikilocytosis, hereditary

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Elliptocytosis 2

Benign:1

Jan 13, 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

.;D

MetaRNN

Benign

0.0097

T;T

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

4.6

PrimateAI

Uncertain

0.48

PROVEAN

Uncertain

-3.5

D;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.42

MPC

0.23

ClinPred

0.053

GERP RS

5.2

Varity_R

0.59

gMVP

0.30

Mutation Taster

=80/20

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