rs147235045

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001355436.2(SPTB):c.3015C>T(p.Ala1005Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,784 control chromosomes in the GnomAD database, including 5 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 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 5 hom. )

Consequence

SPTB
NM_001355436.2 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -8.92

Publications

1 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 14-64786950-G-A is Benign according to our data. Variant chr14-64786950-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 257107.

BP7

Synonymous conserved (PhyloP=-8.92 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00158 (2305/1461538) while in subpopulation MID AF = 0.00347 (20/5768). AF 95% confidence interval is 0.00288. There are 5 homozygotes in GnomAdExome4. There are 1183 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2 link	c.3015C>T	p.Ala1005Ala	synonymous_variant	Exon 16 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTB	ENST00000644917.1 link	c.3015C>T	p.Ala1005Ala	synonymous_variant	Exon 16 of 36		NM_001355436.2	ENSP00000495909.1	P11277-2
SPTB	ENST00000389722.7 link	c.3015C>T	p.Ala1005Ala	synonymous_variant	Exon 15 of 35	2		ENSP00000374372.3	P11277-2
SPTB	ENST00000389720.4 link	c.3015C>T	p.Ala1005Ala	synonymous_variant	Exon 16 of 32	5		ENSP00000374370.4	P11277-1

Frequencies

GnomAD3 genomes

AF:

0.00108

AC:

164

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00129

AC:

324

AN:

251132

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000520

Gnomad ASJ exome

AF:

0.00159

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00158

AC:

2305

AN:

1461538

Hom.:

Cov.:

AF XY:

0.00163

AC XY:

1183

AN XY:

727102

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000604

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00319

AC:

275

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53068

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00165

AC:

1830

AN:

1112008

Other (OTH)

AF:

0.00164

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

166

332

497

663

829

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00107

AC:

163

AN:

152246

Hom.:

Cov.:

AF XY:

0.00103

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41542

American (AMR)

AF:

0.00157

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00270

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00151

AC:

103

AN:

68010

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00125

Hom.:

Bravo

AF:

0.00116

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SPTB: BP4, BP7 -

Sep 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Elliptocytosis

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spherocytosis, Dominant

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.85

CADD

Benign

0.52

(source)

DANN

Benign

0.75

PhyloP100

-8.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=69/31

polymorphism

(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