rs144787939

Variant names:

• chr9-128579718-T-G
• rs144787939
• NM_001130438.3:c.1303T>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_001375318.1(SPTAN1):​c.1339T>G​(p.Ser447Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,010 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: SPTAN1 NM_001375318.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:11
• Conservation: PhyloP100: 7.61
• Publications: 11 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011061877).
• BP6: Variant 9-128579718-T-G is Benign according to our data. Variant chr9-128579718-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159993.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 = 0.00209 (319/152286) while in subpopulation NFE AF = 0.00404 (275/68028). AF 95% confidence interval is 0.00365. There are 1 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 319 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001375318.1. 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.1303T>G	p.Ser435Ala	missense	Exon 10 of 57	NP_001123910.1
	SPTAN1	NM_001375318.1		c.1339T>G	p.Ser447Ala	missense	Exon 11 of 59	NP_001362247.1
	SPTAN1	NM_001375310.1		c.1303T>G	p.Ser435Ala	missense	Exon 10 of 58	NP_001362239.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.1303T>G	p.Ser435Ala	missense	Exon 10 of 57	ENSP00000361824.4
	SPTAN1	ENST00000372731.8	TSL:1	c.1303T>G	p.Ser435Ala	missense	Exon 10 of 56	ENSP00000361816.4
	SPTAN1	ENST00000358161.9	TSL:1	c.1303T>G	p.Ser435Ala	missense	Exon 10 of 55	ENSP00000350882.6

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152168 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00404

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00224 AC: 562 AN: 251342 AF XY: 0.00223

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00437

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00301 AC: 4394 AN: 1461724 Hom.: 13 Cov.: 31 AF XY: 0.00286 AC XY: 2083 AN XY: 727168

African (AFR) AF: 0.000418 AC: 14 AN: 33474

American (AMR) AF: 0.000358 AC: 16 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86250

European-Finnish (FIN) AF: 0.00142 AC: 76 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00375 AC: 4166 AN: 1111896

Other (OTH) AF: 0.00164 AC: 99 AN: 60390

GnomAD4 genome AF: 0.00209 AC: 319 AN: 152286 Hom.: 1 Cov.: 31 AF XY: 0.00183 AC XY: 136 AN XY: 74458

African (AFR) AF: 0.000529 AC: 22 AN: 41560

American (AMR) AF: 0.000262 AC: 4 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00404 AC: 275 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00285 Hom.: 4

Bravo AF: 0.00180

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00266 AC: 323

EpiCase AF: 0.00284

EpiControl AF: 0.00344

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	2	Developmental and epileptic encephalopathy, 5 (2)
-	-	1	Developmental and epileptic encephalopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (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
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.65	N
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.30	T
Sift4G	Benign	0.43	T
Polyphen		0.078	B
Vest4		0.58
MVP		0.52
MPC		0.68
ClinPred		0.034	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.16
Mutation Taster		=64/36	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: rs144787939; hg19: chr9-131341997; COSMIC: COSV108182809; COSMIC: COSV108182809;