rs1554752325

Variant names:

• chr9-128594376-A-G
• rs1554752325
• NM_001130438.3:c.3414+3A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP3 BP6_Moderate

The NM_001130438.3(SPTAN1):​c.3414+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000675 in 148,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0000067 (0 hom., cov: 32)
• Consequence: SPTAN1 NM_001130438.3 splice_region, intron
• Scores: Splicing: ADA: 0.9966
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• BP6: Variant 9-128594376-A-G is Benign according to our data. Variant chr9-128594376-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 530590.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	NM_001130438.3	MANE Select	c.3414+3A>G		splice_region intron	N/A	NP_001123910.1
	SPTAN1	NM_001375318.1		c.3450+3A>G		splice_region intron	N/A	NP_001362247.1
	SPTAN1	NM_001375310.1		c.3414+3A>G		splice_region intron	N/A	NP_001362239.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.3414+3A>G		splice_region intron	N/A	ENSP00000361824.4
	SPTAN1	ENST00000372731.8	TSL:1	c.3414+3A>G		splice_region intron	N/A	ENSP00000361816.4
	SPTAN1	ENST00000358161.9	TSL:1	c.3354+3A>G		splice_region intron	N/A	ENSP00000350882.6

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000149

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148166 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 71998

African (AFR) AF: 0.00 AC: 0 AN: 40466

American (AMR) AF: 0.00 AC: 0 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.00 AC: 0 AN: 4642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000149 AC: 1 AN: 67044

Other (OTH) AF: 0.00 AC: 0 AN: 2050

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Benign	0.95
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.25		Position offset: -36

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

Other links and lift over

dbSNP: rs1554752325; hg19: chr9-131356655;