rs77358650

Variant names:

• chr9-128580928-G-A
• rs77358650
• NM_001130438.3:c.1330G>A

Your query was ambiguous. Multiple possible variants found:

• chr9-128580928-G-A
• chr9-128580928-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130438.3(SPTAN1):​c.1330G>A​(p.Val444Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,612,962 control chromosomes in the GnomAD database, including 142 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V444L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (10 hom., cov: 31)
  • Exomes 𝑓: 0.0032 (132 hom.)
• Consequence: SPTAN1 NM_001130438.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:8
• Conservation: PhyloP100: -0.0890
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004676819).
• BP6: Variant 9-128580928-G-A is Benign according to our data. Variant chr9-128580928-G-A is described in ClinVar as Benign. ClinVar VariationId is 139269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0516 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.1330G>A	p.Val444Ile	missense	Exon 11 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.1366G>A	p.Val456Ile	missense	Exon 12 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.1330G>A	p.Val444Ile	missense	Exon 11 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.1330G>A	p.Val444Ile	missense	Exon 11 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.1330G>A	p.Val444Ile	missense	Exon 11 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.1330G>A	p.Val444Ile	missense	Exon 11 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152194 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.0407

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00522 AC: 1311 AN: 251106 AF XY: 0.00581

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.0290

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00315 AC: 4604 AN: 1460650 Hom.: 132 Cov.: 31 AF XY: 0.00363 AC XY: 2635 AN XY: 726642

African (AFR) AF: 0.000628 AC: 21 AN: 33444

American (AMR) AF: 0.000313 AC: 14 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26132

East Asian (EAS) AF: 0.0535 AC: 2123 AN: 39696

South Asian (SAS) AF: 0.0208 AC: 1789 AN: 86200

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53220

Middle Eastern (MID) AF: 0.00222 AC: 11 AN: 4944

European-Non Finnish (NFE) AF: 0.000185 AC: 206 AN: 1111992

Other (OTH) AF: 0.00494 AC: 298 AN: 60298

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152312 Hom.: 10 Cov.: 31 AF XY: 0.00332 AC XY: 247 AN XY: 74464

African (AFR) AF: 0.000770 AC: 32 AN: 41572

American (AMR) AF: 0.000457 AC: 7 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3470

East Asian (EAS) AF: 0.0404 AC: 209 AN: 5174

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4828

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68036

Other (OTH) AF: 0.00380 AC: 8 AN: 2108

Alfa AF: 0.00144 Hom.: 10

Bravo AF: 0.00165

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00566 AC: 687

Asia WGS AF: 0.0520 AC: 181 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Developmental and epileptic encephalopathy, 5 (2)
-	-	2	not specified (2)
1	-	-	Abnormal brain morphology (1)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.013
DANN	Benign	0.83
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.089
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.038
Sift	Benign	0.66	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.52
MVP		0.17
MPC		0.63
ClinPred		0.0034	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.017
Mutation Taster		=94/6	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs77358650; hg19: chr9-131343207; COSMIC: COSV63987177; COSMIC: COSV63987177;