rs1287628912

Variant names:

• chr9-128617987-G-A
• rs1287628912
• NM_001130438.3:c.5479G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS1

The NM_001130438.3(SPTAN1):​c.5479G>A​(p.Gly1827Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000197 in 152,268 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 Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 31)
• Consequence: SPTAN1 NM_001130438.3 missense, splice_region
• Scores: Splicing: ADA: 0.9991
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.38
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, G2P, Ambry Genetics
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neuronopathy, distal hereditary motor, autosomal dominant 11

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spastic paraplegia

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000197 (3/152268) while in subpopulation EAS AF = 0.00058 (3/5172). AF 95% confidence interval is 0.000157. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	NM_001130438.3	MANE Select	c.5479G>A	p.Gly1827Ser	missense splice_region	Exon 43 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.5515G>A	p.Gly1839Ser	missense splice_region	Exon 44 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.5479G>A	p.Gly1827Ser	missense splice_region	Exon 43 of 58	NP_001362239.1	A0A994J6W3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.5479G>A	p.Gly1827Ser	missense splice_region	Exon 43 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.5464G>A	p.Gly1822Ser	missense splice_region	Exon 42 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.5404G>A	p.Gly1802Ser	missense splice_region	Exon 41 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74462

African (AFR) AF: 0.00 AC: 0 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.081	T
Eigen	Benign	0.062
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		6.4
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.085
Sift	Benign	0.50	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.28		Loss of catalytic residue at P1818 (P = 0.0711)
MVP		0.24
MPC		0.77
ClinPred		0.85	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.14
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1287628912; hg19: chr9-131380266;