rs200543425

Variant names:

• chr9-128605029-T-G
• rs200543425
• NM_001130438.3:c.3720-5T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130438.3(SPTAN1):​c.3720-5T>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 0.00282 in 1,614,138 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 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, intron
• Scores: Splicing: ADA: 0.6219
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -0.222
• 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

ENSG00000297241 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 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 Benign/Likely_benign. ClinVar VariationId is 167720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00178 (271/152272) while in subpopulation NFE AF = 0.00297 (202/68024). AF 95% confidence interval is 0.00263. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 10 AD,AR gene

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.3720-5T>G		splice_region intron	N/A	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.3756-5T>G		splice_region intron	N/A	NP_001362247.1
	SPTAN1	NM_001375310.1		c.3720-5T>G		splice_region intron	N/A	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.3720-5T>G		splice_region intron	N/A	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.3720-5T>G		splice_region intron	N/A	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.3660-5T>G		splice_region intron	N/A	ENSP00000350882.6	Q13813-3

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

GnomAD2 exomes AF: 0.00147 AC: 369 AN: 251460 AF XY: 0.00151

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 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

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.00192 AC: 86 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00358 AC: 3979 AN: 1111990

Other (OTH) AF: 0.00321 AC: 194 AN: 60396

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

African (AFR) AF: 0.000457 AC: 19 AN: 41560

American (AMR) AF: 0.00281 AC: 43 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00297 AC: 202 AN: 68024

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00239 Hom.: 2

Bravo AF: 0.00224

EpiCase AF: 0.00393

EpiControl AF: 0.00338

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Developmental and epileptic encephalopathy, 5 (2)
-	-	2	not specified (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
1	-	-	Self-limited epilepsy with centrotemporal spikes (1)
-	-	1	SPTAN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.36
PhyloP100		-0.22
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200543425; hg19: chr9-131367308;