rs200543425

chr9-128605029-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001130438.3(SPTAN1):c.3720-5T>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,614,138 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: SPTAN1 NM_001130438.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.6219
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:11
• Conservation: PhyloP100: -0.222

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-128605029-T-G is Benign according to our data. Variant chr9-128605029-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 167720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128605029-T-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 271 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.3720-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.3720-5T>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130438.3	P3

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00297

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00147 AC: 369 AN: 251460 Hom.: 1 AF XY: 0.00151 AC XY: 205 AN XY: 135910

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00293 AC: 4287 AN: 1461866 Hom.: 10 Cov.: 31 AF XY: 0.00277 AC XY: 2014 AN XY: 727242

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00358

Gnomad4 OTH exome AF: 0.00321

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74460

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00224

EpiCase AF: 0.00393

EpiControl AF: 0.00338

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SPTAN1: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 11, 2018	- -

Developmental and epileptic encephalopathy, 5 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Jul 12, 2022	This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF 0.2% (331/129180) including 1 homozygote (https://gnomad.broadinstitute.org/variant/9-131367308-T-G?dataset=gnomad_r2_1). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:167720). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Childhood epilepsy with centrotemporal spikes Pathogenic:1

Pathogenic, flagged submission

case-control

Bioinformatics Core, Luxembourg Center for Systems Biomedicine

Jan 01, 2017

CAADphred>15 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 28, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2019

This alteration is classified as likely 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

Invitae

Jan 25, 2024

- -

SPTAN1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	8.7
Dann	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.42
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.33		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200543425; hg19: chr9-131367308;