rs3750333

Variant names:

• chr9-128617719-C-A
• rs3750333
• NM_001130438.3:c.5437C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-128617719-C-A
• chr9-128617719-C-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001130438.3(SPTAN1):​c.5437C>A​(p.Arg1813Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.0182 in 1,614,074 control chromosomes in the GnomAD database, including 447 homozygotes. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R1813R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (34 hom., cov: 32)
  • Exomes 𝑓: 0.018 (413 hom.)
• Consequence: SPTAN1 NM_001130438.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.99
• Publications: 7 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 9-128617719-C-A is Benign according to our data. Variant chr9-128617719-C-A is described in ClinVar as Benign. ClinVar VariationId is 160017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

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.5437C>A	p.Arg1813Arg	synonymous	Exon 42 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.5473C>A	p.Arg1825Arg	synonymous	Exon 43 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.5437C>A	p.Arg1813Arg	synonymous	Exon 42 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.5437C>A	p.Arg1813Arg	synonymous	Exon 42 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.5422C>A	p.Arg1808Arg	synonymous	Exon 41 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.5362C>A	p.Arg1788Arg	synonymous	Exon 40 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2588 AN: 152132 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.00418

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.0417

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0803

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0168

GnomAD2 exomes AF: 0.0247 AC: 6195 AN: 251294 AF XY: 0.0233

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0527

Gnomad ASJ exome AF: 0.00715

Gnomad EAS exome AF: 0.0833

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0235

GnomAD4 exome AF: 0.0183 AC: 26752 AN: 1461824 Hom.: 413 Cov.: 39 AF XY: 0.0183 AC XY: 13331 AN XY: 727218

African (AFR) AF: 0.00332 AC: 111 AN: 33474

American (AMR) AF: 0.0507 AC: 2268 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00631 AC: 165 AN: 26136

East Asian (EAS) AF: 0.0902 AC: 3580 AN: 39700

South Asian (SAS) AF: 0.0234 AC: 2016 AN: 86254

European-Finnish (FIN) AF: 0.00594 AC: 317 AN: 53410

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5760

European-Non Finnish (NFE) AF: 0.0153 AC: 16971 AN: 1111980

Other (OTH) AF: 0.0199 AC: 1204 AN: 60388

GnomAD4 genome AF: 0.0170 AC: 2592 AN: 152250 Hom.: 34 Cov.: 32 AF XY: 0.0177 AC XY: 1319 AN XY: 74452

African (AFR) AF: 0.00416 AC: 173 AN: 41556

American (AMR) AF: 0.0419 AC: 641 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.0804 AC: 417 AN: 5184

South Asian (SAS) AF: 0.0245 AC: 118 AN: 4816

European-Finnish (FIN) AF: 0.00368 AC: 39 AN: 10598

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1087 AN: 68014

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0169 Hom.: 106

Bravo AF: 0.0191

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0169

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 5 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	12
DANN	Benign	0.67
PhyloP100		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3750333; hg19: chr9-131379998; COSMIC: COSV63986751; COSMIC: COSV63986751;