Genetic Variant SPTB:p.Ile718Ile (chr14-64793509-T-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001355436.2(SPTB):c.2154A>C(p.Ile718Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,834 control chromosomes in the GnomAD database, including 121,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.44 ( 16184 hom., cov: 32)

Exomes 𝑓: 0.37 ( 105615 hom. )

Consequence

SPTB
NM_001355436.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.30

Publications

14 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 14-64793509-T-G is Benign according to our data. Variant chr14-64793509-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.3 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.643 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTB	NM_001355436.2	MANE Select	c.2154A>C	p.Ile718Ile	synonymous	Exon 14 of 36	NP_001342365.1
SPTB	NM_001024858.4		c.2154A>C	p.Ile718Ile	synonymous	Exon 13 of 35	NP_001020029.1
SPTB	NM_001355437.2		c.2154A>C	p.Ile718Ile	synonymous	Exon 14 of 32	NP_001342366.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTB	ENST00000644917.1	MANE Select	c.2154A>C	p.Ile718Ile	synonymous	Exon 14 of 36	ENSP00000495909.1
SPTB	ENST00000389722.7	TSL:2	c.2154A>C	p.Ile718Ile	synonymous	Exon 13 of 35	ENSP00000374372.3
SPTB	ENST00000389720.4	TSL:5	c.2154A>C	p.Ile718Ile	synonymous	Exon 14 of 32	ENSP00000374370.4

Frequencies

GnomAD3 genomes

AF:

0.440

AC:

66863

AN:

151936

Hom.:

16156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.650

Gnomad AMI

AF:

0.481

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.431

Gnomad EAS

AF:

0.195

Gnomad SAS

AF:

0.505

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.364

Gnomad OTH

AF:

0.420

GnomAD2 exomes

AF:

0.378

AC:

94946

AN:

250852

AF XY:

0.384

show subpopulations

Gnomad AFR exome

AF:

0.654

Gnomad AMR exome

AF:

0.273

Gnomad ASJ exome

AF:

0.434

Gnomad EAS exome

AF:

0.183

Gnomad FIN exome

AF:

0.336

Gnomad NFE exome

AF:

0.372

Gnomad OTH exome

AF:

0.380

GnomAD4 exome

AF:

0.373

AC:

545365

AN:

1461780

Hom.:

105615

Cov.:

AF XY:

0.378

AC XY:

274552

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.664

AC:

22240

AN:

33480

American (AMR)

AF:

0.285

AC:

12757

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.445

AC:

11635

AN:

26136

East Asian (EAS)

AF:

0.209

AC:

8290

AN:

39700

South Asian (SAS)

AF:

0.500

AC:

43163

AN:

86256

European-Finnish (FIN)

AF:

0.337

AC:

17966

AN:

53330

Middle Eastern (MID)

AF:

0.435

AC:

2511

AN:

5768

European-Non Finnish (NFE)

AF:

0.362

AC:

403033

AN:

1111996

Other (OTH)

AF:

0.394

AC:

23770

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

25563

51126

76689

102252

127815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12792

25584

38376

51168

63960

<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:

0.440

AC:

66939

AN:

152054

Hom.:

16184

Cov.:

AF XY:

0.438

AC XY:

32540

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.650

AC:

26948

AN:

41472

American (AMR)

AF:

0.343

AC:

5237

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.431

AC:

1495

AN:

3468

East Asian (EAS)

AF:

0.195

AC:

1008

AN:

5166

South Asian (SAS)

AF:

0.504

AC:

2426

AN:

4818

European-Finnish (FIN)

AF:

0.345

AC:

3651

AN:

10570

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.364

AC:

24722

AN:

67958

Other (OTH)

AF:

0.420

AC:

886

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1851

3702

5554

7405

9256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<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:

0.395

Hom.:

27158

Bravo

AF:

0.446

Asia WGS

AF:

0.407

AC:

1415

AN:

3478

EpiCase

AF:

0.379

EpiControl

AF:

0.385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 05, 2021

GeneDx

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

Nov 29, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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

Hereditary spherocytosis type 2

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.2

(source)

DANN

Benign

0.70

PhyloP100

-1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over