rs28525570

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_003126.4(SPTA1):c.6531-12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.27 in 1,602,240 control chromosomes in the GnomAD database, including 60,252 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 0.25 ( 5121 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55131 hom. )

Consequence

SPTA1
NM_003126.4 intron

Scores

Splicing: ADA: 0.0004991

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:6

Conservation

PhyloP100: 0.574

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 links:

SPTA1 (HGNC:):

SPTA1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 1-158618068-G-A is Benign according to our data. Variant chr1-158618068-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 258954.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=3, Likely_pathogenic=1}.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
SPTA1	NM_003126.4 linkuse as main transcript	c.6531-12C>T	intron_variant	ENST00000643759.2	NP_003117.2	P02549-1
SPTA1	XM_011509916.3 linkuse as main transcript	c.6531-12C>T	intron_variant		XP_011508218.1	P02549-1
SPTA1	XM_011509917.4 linkuse as main transcript	c.6531-480C>T	intron_variant		XP_011508219.1
SPTA1	XM_047428883.1 linkuse as main transcript	c.6210-12C>T	intron_variant		XP_047284839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTA1	ENST00000643759.2 linkuse as main transcript	c.6531-12C>T		intron_variant			NM_003126.4	ENSP00000495214.1		P02549-1
SPTA1	ENST00000492934.1 linkuse as main transcript	n.34C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.254

AC:

38595

AN:

151962

Hom.:

5120

Cov.:

show subpopulations

Gnomad AFR

AF:

0.199

Gnomad AMI

AF:

0.229

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.185

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.309

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.288

Gnomad OTH

AF:

0.261

GnomAD3 exomes

AF:

0.254

AC:

63402

AN:

249186

Hom.:

8413

AF XY:

0.259

AC XY:

35021

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.171

Gnomad ASJ exome

AF:

0.349

Gnomad EAS exome

AF:

0.185

Gnomad SAS exome

AF:

0.250

Gnomad FIN exome

AF:

0.292

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.259

GnomAD4 exome

AF:

0.271

AC:

393274

AN:

1450160

Hom.:

55131

Cov.:

AF XY:

0.272

AC XY:

196331

AN XY:

721926

show subpopulations

Gnomad4 AFR exome

AF:

0.197

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.349

Gnomad4 EAS exome

AF:

0.203

Gnomad4 SAS exome

AF:

0.245

Gnomad4 FIN exome

AF:

0.289

Gnomad4 NFE exome

AF:

0.280

Gnomad4 OTH exome

AF:

0.263

GnomAD4 genome

AF:

0.254

AC:

38604

AN:

152080

Hom.:

5121

Cov.:

AF XY:

0.255

AC XY:

18981

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.198

Gnomad4 AMR

AF:

0.218

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.185

Gnomad4 SAS

AF:

0.245

Gnomad4 FIN

AF:

0.309

Gnomad4 NFE

AF:

0.288

Gnomad4 OTH

AF:

0.264

Alfa

AF:

0.214

Hom.:

769

Bravo

AF:

0.242

Asia WGS

AF:

0.209

AC:

729

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	Commonly referred to as the AlphaLELY allele, this variant is a low expression allele that results in partial skipping of exon 46 and expression of hereditary elliptocytosis when in trans with a pathogenic SPTA1 variant (Wilmotte et al., 1999); This variant has been reported multiple times in association with hereditary elliptocytosis when present in trans with a pathogenic SPTA1 variant (Russo et al., 2018; Aggarwal et al., 2020; Suzuki et al., 2021) This variant is associated with the following publications: (PMID: 10192450, 29396846, 31602632, 32287101, 29484404, 30298500, 32581362) -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SPTA1: BS1, BS2 -

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Hemolytic anemia

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

- -

Elliptocytosis 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary spherocytosis type 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Pyropoikilocytosis, hereditary

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.80

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00050

dbscSNV1_RF

Benign

0.26

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over