rs587784440

chr9-128632260-GGGACCAGCT-Gchr9-128632260-GGGACCAGCT-GGGACCAGCTGGACCAGCT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_001130438.3(SPTAN1):c.6908_6916del(p.Asp2303_Leu2305del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTAN1 NM_001130438.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.59

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001130438.3
• PM4: Nonframeshift variant in NON repetitive region in NM_001130438.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-128632260-GGGACCAGCT-G is Pathogenic according to our data. Variant chr9-128632260-GGGACCAGCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.6908_6916del	p.Asp2303_Leu2305del	inframe_deletion	53/57	ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.6908_6916del	p.Asp2303_Leu2305del	inframe_deletion	53/57	1	NM_001130438.3	P3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2023	In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27864847, 34590414) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 06, 2023	- -

Developmental and epileptic encephalopathy, 5 Pathogenic:2

Pathogenic, no assertion criteria provided	provider interpretation	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Sep 01, 2017	- -

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This variant is not present in population databases (gnomAD no frequency). This variant, c.6908_6916del, results in the deletion of 3 amino acid(s) of the SPTAN1 protein (p.Asp2303_Leu2305del), but otherwise preserves the integrity of the reading frame. This variant has been observed in individual(s) with clinical features of SPTAN1-related conditions (PMID: 27864847, 34590414; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 207380). For these reasons, this variant has been classified as Pathogenic. -

Developmental delay with or without epilepsy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 18, 2023

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Apr 26, 2021

PP5_strong;PM1_moderate;PM2_supporting;PM6_moderate;PP3_supporting;BP3_supporting -

Focal epilepsy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neurogenetics Laboratory - MEYER, AOU Meyer

Nov 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784440; hg19: chr9-131394539;