rs4902312

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001355436.2(SPTB):c.4564-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,609,878 control chromosomes in the GnomAD database, including 4,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 294 hom., cov: 33)

Exomes 𝑓: 0.073 ( 4259 hom. )

Consequence

SPTB
NM_001355436.2 splice_region, intron

Scores

Splicing: ADA: 0.00002860

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -4.71

Publications

7 publications found

Variant links:

Genes affected

SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

SPTB Gene-Disease associations (from GenCC):

hereditary spherocytosis type 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
elliptocytosis 3
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary elliptocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary spherocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

SPTB 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 (BayesDel_noAF=-0.78).

BP6

Variant 14-64775407-C-T is Benign according to our data. Variant chr14-64775407-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2 link	c.4564-4G>A		splice_region_variant, intron_variant	Intron 22 of 35	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTB	ENST00000644917.1 link	c.4564-4G>A	splice_region_variant, intron_variant	Intron 22 of 35		NM_001355436.2	ENSP00000495909.1	P11277-2
SPTB	ENST00000553938.5 link	c.559-4G>A	splice_region_variant, intron_variant	Intron 3 of 17	1		ENSP00000451324.1	H0YJE6
SPTB	ENST00000389722.7 link	c.4564-4G>A	splice_region_variant, intron_variant	Intron 21 of 34	2		ENSP00000374372.3	P11277-2
SPTB	ENST00000389720.4 link	c.4564-4G>A	splice_region_variant, intron_variant	Intron 22 of 31	5		ENSP00000374370.4	P11277-1

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

8775

AN:

152202

Hom.:

294

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0533

Gnomad ASJ

AF:

0.0548

Gnomad EAS

AF:

0.0200

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.0769

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0848

Gnomad OTH

AF:

0.0440

GnomAD2 exomes

AF:

0.0597

AC:

14713

AN:

246310

AF XY:

0.0602

show subpopulations

Gnomad AFR exome

AF:

0.0163

Gnomad AMR exome

AF:

0.0407

Gnomad ASJ exome

AF:

0.0506

Gnomad EAS exome

AF:

0.0260

Gnomad FIN exome

AF:

0.0754

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.0590

GnomAD4 exome

AF:

0.0729

AC:

106225

AN:

1457558

Hom.:

4259

Cov.:

AF XY:

0.0720

AC XY:

52121

AN XY:

724344

show subpopulations

African (AFR)

AF:

0.0158

AC:

527

AN:

33410

American (AMR)

AF:

0.0436

AC:

1944

AN:

44594

Ashkenazi Jewish (ASJ)

AF:

0.0517

AC:

1346

AN:

26028

East Asian (EAS)

AF:

0.0166

AC:

657

AN:

39596

South Asian (SAS)

AF:

0.0302

AC:

2600

AN:

86056

European-Finnish (FIN)

AF:

0.0783

AC:

4152

AN:

52996

Middle Eastern (MID)

AF:

0.0385

AC:

221

AN:

5734

European-Non Finnish (NFE)

AF:

0.0819

AC:

90816

AN:

1108938

Other (OTH)

AF:

0.0658

AC:

3962

AN:

60206

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

5540

11081

16621

22162

27702

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0576

AC:

8777

AN:

152320

Hom.:

294

Cov.:

AF XY:

0.0576

AC XY:

4294

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0190

AC:

791

AN:

41580

American (AMR)

AF:

0.0532

AC:

814

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

190

AN:

3470

East Asian (EAS)

AF:

0.0200

AC:

104

AN:

5194

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4830

European-Finnish (FIN)

AF:

0.0769

AC:

815

AN:

10604

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0848

AC:

5769

AN:

68020

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

454

908

1363

1817

2271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0722

Hom.:

350

Bravo

AF:

0.0534

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

EpiCase

AF:

0.0760

EpiControl

AF:

0.0760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 12, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25525159, 19538529, 27884173, 27354418) -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Elliptocytosis

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spherocytosis, Dominant

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.34

(source)

DANN

Benign

0.68

PhyloP100

-4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000029

dbscSNV1_RF

Benign

0.020

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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rs4902312

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