NM_001130438.3:c.5552C>T

Variant names:

• chr9-128618060-C-T
• rs11543347
• NM_001130438.3:c.5552C>T

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.5552C>T​(p.Ala1851Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000694 in 1,612,654 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1851A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00042 (2 hom.)
• Consequence: SPTAN1 NM_001130438.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.53
• Publications: 4 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=0.01095441).
• BP6: Variant 9-128618060-C-T is Benign according to our data. Variant chr9-128618060-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 139302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00333 (507/152228) while in subpopulation AFR AF = 0.0113 (468/41534). AF 95% confidence interval is 0.0104. There are 3 homozygotes in GnomAd4. There are 245 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 507 AD 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.5552C>T	p.Ala1851Val	missense	Exon 43 of 57	NP_001123910.1	Q13813-2
	SPTAN1	NM_001375318.1		c.5588C>T	p.Ala1863Val	missense	Exon 44 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.5552C>T	p.Ala1851Val	missense	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.5552C>T	p.Ala1851Val	missense	Exon 43 of 57	ENSP00000361824.4	Q13813-2
	SPTAN1	ENST00000372731.8	TSL:1	c.5537C>T	p.Ala1846Val	missense	Exon 42 of 56	ENSP00000361816.4	Q13813-1
	SPTAN1	ENST00000358161.9	TSL:1	c.5477C>T	p.Ala1826Val	missense	Exon 41 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152112 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.000132

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000992 AC: 246 AN: 248080 AF XY: 0.000750

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000419 AC: 612 AN: 1460426 Hom.: 2 Cov.: 34 AF XY: 0.000366 AC XY: 266 AN XY: 726544

African (AFR) AF: 0.0128 AC: 427 AN: 33468

American (AMR) AF: 0.000917 AC: 41 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5676

European-Non Finnish (NFE) AF: 0.0000917 AC: 102 AN: 1111922

Other (OTH) AF: 0.000614 AC: 37 AN: 60280

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152228 Hom.: 3 Cov.: 31 AF XY: 0.00329 AC XY: 245 AN XY: 74434

African (AFR) AF: 0.0113 AC: 468 AN: 41534

American (AMR) AF: 0.00151 AC: 23 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.000662 Hom.: 2

Bravo AF: 0.00386

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Developmental and epileptic encephalopathy, 5 (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	SPTAN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.23
Sift	Benign	0.10	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.57
MVP		0.54
MPC		0.86
ClinPred		0.037	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.30
Mutation Taster		=97/3	polymorphism

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: rs11543347; hg19: chr9-131380339;