14-64782435-T-C

Position:

chr14-64782435-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001355436.2(SPTB):c.4121A>G(p.His1374Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,614,044 control chromosomes in the GnomAD database, including 1,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1374C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 97 hom., cov: 32)

Exomes 𝑓: 0.033 ( 944 hom. )

Consequence

SPTB
NM_001355436.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.503

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020920336).

BP6

Variant 14-64782435-T-C is Benign according to our data. Variant chr14-64782435-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64782435-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2 linkuse as main transcript	c.4121A>G	p.His1374Arg	missense_variant	20/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1 linkuse as main transcript	c.4121A>G	p.His1374Arg	missense_variant	20/36		NM_001355436.2	P1	P11277-2
SPTB	ENST00000553938.5 linkuse as main transcript	c.116A>G	p.His39Arg	missense_variant	1/18	1
SPTB	ENST00000389722.7 linkuse as main transcript	c.4121A>G	p.His1374Arg	missense_variant	19/35	2		P1	P11277-2
SPTB	ENST00000389720.4 linkuse as main transcript	c.4121A>G	p.His1374Arg	missense_variant	20/32	5			P11277-1

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5272

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0447

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.0215

Gnomad ASJ

AF:

0.0507

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0665

Gnomad FIN

AF:

0.0260

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0307

GnomAD3 exomes

AF:

0.0328

AC:

8254

AN:

251390

Hom.:

189

AF XY:

0.0348

AC XY:

4724

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.0444

Gnomad AMR exome

AF:

0.0208

Gnomad ASJ exome

AF:

0.0507

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0651

Gnomad FIN exome

AF:

0.0255

Gnomad NFE exome

AF:

0.0307

Gnomad OTH exome

AF:

0.0437

GnomAD4 exome

AF:

0.0326

AC:

47651

AN:

1461834

Hom.:

944

Cov.:

AF XY:

0.0339

AC XY:

24677

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.0463

Gnomad4 AMR exome

AF:

0.0216

Gnomad4 ASJ exome

AF:

0.0522

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0680

Gnomad4 FIN exome

AF:

0.0270

Gnomad4 NFE exome

AF:

0.0308

Gnomad4 OTH exome

AF:

0.0335

GnomAD4 genome

AF:

0.0346

AC:

5271

AN:

152210

Hom.:

Cov.:

AF XY:

0.0344

AC XY:

2559

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.0446

Gnomad4 AMR

AF:

0.0214

Gnomad4 ASJ

AF:

0.0507

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.0664

Gnomad4 FIN

AF:

0.0260

Gnomad4 NFE

AF:

0.0327

Gnomad4 OTH

AF:

0.0303

Alfa

AF:

0.0311

Hom.:

159

Bravo

AF:

0.0338

TwinsUK

AF:

0.0305

AC:

113

ALSPAC

AF:

0.0306

AC:

118

ESP6500AA

AF:

0.0443

AC:

195

ESP6500EA

AF:

0.0316

AC:

272

ExAC

AF:

0.0340

AC:

4123

Asia WGS

AF:

0.0290

AC:

100

AN:

3478

EpiCase

AF:

0.0320

EpiControl

AF:

0.0302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Elliptocytosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.46

DANN

Benign

0.17

DEOGEN2

Benign

0.0028

.;.;.;T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.20

.;.;T;T;.;T

MetaRNN

Benign

0.0021

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.54

N;N;N;.;N;N

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.59

N;.;N;N;N;N

REVEL

Benign

0.018

Sift

Benign

1.0

T;.;T;T;T;T

Sift4G

Benign

0.83

T;.;T;T;T;T

Polyphen

0.0

.;.;.;.;B;B

Vest4

0.0060

MPC

0.23

ClinPred

0.0011

GERP RS

-3.2

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.029

gMVP

0.12

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

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