rs140076136

Positions:

chr9-128577380-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The ENST00000372739.7(SPTAN1):c.959G>A(p.Arg320His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R320C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

SPTAN1
ENST00000372739.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.76

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 Likely_benign. Variant got -6 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=0.25784418).

BP6

Variant 9-128577380-G-A is Benign according to our data. Variant chr9-128577380-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207315.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTAN1	NM_001130438.3 linkuse as main transcript	c.959G>A	p.Arg320His	missense_variant	8/57	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.959G>A	p.Arg320His	missense_variant	8/57	1	NM_001130438.3	ENSP00000361824	P3	Q13813-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251308

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

223

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000112

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000181

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2012	p.Arg320His (CGC>CAC): c.959 G>A in exon 8 of the SPTAN1 gene (NM_001130438.1) The Arg320His missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project did not identify Arg320His in approximately 5000 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. Arg320His alters a position that is highly conserved in the alpha-II spectrin protein, and multiple in silico algorithms predict this variant may be damaging to protein structure/function. However, previously reported pathogenic missense mutations in SPTAN1 are located within the last four spectrin repeats that are essential for dimerization (Saitsu et al., 2010), and the Arg320 residue is outside this region. Additionally, the amino acid substitution is conservative, as Arginine and Histidine are both positively charged amino acids. Therefore, based on the currently available information it is unclear whether Arg320His is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Early infantile epileptic encephalopathy with suppression bursts

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Developmental and epileptic encephalopathy, 5

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

T;.;.;.;.

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.2

M;.;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.5

D;.;D;D;.

REVEL

Uncertain

0.38

Sift

Uncertain

0.022

D;.;D;D;.

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

D;.;P;B;.

Vest4

0.34

MVP

0.60

MPC

1.1

ClinPred

0.66

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.33

gMVP

0.36

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