rs77358650

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001130438.3(SPTAN1):c.1330G>A(p.Val444Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,612,962 control chromosomes in the GnomAD database, including 142 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 10 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 132 hom. )

Consequence

SPTAN1
NM_001130438.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts P:1U:1B:8

Conservation

PhyloP100: -0.0890

Variant links:

Genes affected

SPTAN1 (HGNC:11273): (spectrin alpha, non-erythrocytic 1) Spectrins are a family of filamentous cytoskeletal proteins that function as essential scaffold proteins that stabilize the plasma membrane and organize intracellular organelles. Spectrins are composed of alpha and beta dimers that associate to form tetramers linked in a head-to-head arrangement. This gene encodes an alpha spectrin that is specifically expressed in nonerythrocytic cells. The encoded protein has been implicated in other cellular functions including DNA repair and cell cycle regulation. Mutations in this gene are the cause of early infantile epileptic encephalopathy-5. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Sep 2010]

SPTAN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPTAN1. . Gene score misZ 5.523 (greater than the threshold 3.09). Trascript score misZ 7.9287 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, 5, developmental and epileptic encephalopathy, West syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.004676819).

BP6

Variant 9-128580928-G-A is Benign according to our data. Variant chr9-128580928-G-A is described in ClinVar as [Benign]. Clinvar id is 139269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128580928-G-A is described in Lovd as [Pathogenic]. Variant chr9-128580928-G-A is described in Lovd as [Benign]. Variant chr9-128580928-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3 linkuse as main transcript	c.1330G>A	p.Val444Ile	missense_variant	11/57	ENST00000372739.7	NP_001123910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTAN1	ENST00000372739.7 linkuse as main transcript	c.1330G>A	p.Val444Ile	missense_variant	11/57	1	NM_001130438.3	ENSP00000361824	P3	Q13813-2

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.0407

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00522

AC:

1311

AN:

251106

Hom.:

AF XY:

0.00581

AC XY:

788

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.0290

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.000187

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00315

AC:

4604

AN:

1460650

Hom.:

132

Cov.:

AF XY:

0.00363

AC XY:

2635

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00513

Gnomad4 EAS exome

AF:

0.0535

Gnomad4 SAS exome

AF:

0.0208

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000185

Gnomad4 OTH exome

AF:

0.00494

GnomAD4 genome

AF:

0.00282

AC:

430

AN:

152312

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.0404

Gnomad4 SAS

AF:

0.0282

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00165

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00566

AC:

687

Asia WGS

AF:

0.0520

AC:

181

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SPTAN1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2018	This variant is associated with the following publications: (PMID: 26539891, 31180159) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2015	- -

Developmental and epileptic encephalopathy, 5

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Abnormal brain morphology

Pathogenic:1

Likely pathogenic, flagged submission

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.013

DANN

Benign

0.83

DEOGEN2

Benign

0.096

T;.;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.59

T;T;T;T;T

MetaRNN

Benign

0.0047

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.90

N;.;N;N;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.23

N;.;N;N;.

REVEL

Benign

0.038

Sift

Benign

0.66

T;.;T;T;.

Sift4G

Benign

0.35

T;T;T;T;T

Polyphen

0.0010

B;.;B;B;.

Vest4

0.52

MVP

0.17

MPC

0.63

ClinPred

0.0034

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.015

gMVP

0.017

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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