dbSNP rs11543345: SPTAN1:p.Ala1975Ala (chr9-128624420-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001130438.3(SPTAN1):c.5925G>A(p.Ala1975Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,004 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 20 hom., cov: 32)

Exomes 𝑓: 0.00086 ( 17 hom. )

Consequence

SPTAN1
NM_001130438.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.520

Publications

1 publications found

Variant links:

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

SPTAN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 9-128624420-G-A is Benign according to our data. Variant chr9-128624420-G-A is described in ClinVar as Benign. ClinVar VariationId is 139305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.52 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00751 (1144/152304) while in subpopulation AFR AF = 0.0262 (1087/41562). AF 95% confidence interval is 0.0249. There are 20 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1144 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTAN1	NM_001130438.3	MANE Select	c.5925G>A	p.Ala1975Ala	synonymous	Exon 46 of 57	NP_001123910.1	Q13813-2
SPTAN1	NM_001375318.1		c.5961G>A	p.Ala1987Ala	synonymous	Exon 47 of 59	NP_001362247.1
SPTAN1	NM_001375310.1		c.5925G>A	p.Ala1975Ala	synonymous	Exon 46 of 58	NP_001362239.1	A0A994J6W3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SPTAN1	ENST00000372739.7	TSL:1 MANE Select	c.5925G>A	p.Ala1975Ala	synonymous	Exon 46 of 57	ENSP00000361824.4	Q13813-2
SPTAN1	ENST00000372731.8	TSL:1	c.5910G>A	p.Ala1970Ala	synonymous	Exon 45 of 56	ENSP00000361816.4	Q13813-1
SPTAN1	ENST00000358161.9	TSL:1	c.5850G>A	p.Ala1950Ala	synonymous	Exon 44 of 55	ENSP00000350882.6	Q13813-3

Frequencies

GnomAD3 genomes

AF:

0.00752

AC:

1144

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00203

AC:

511

AN:

251186

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.000857

AC:

1253

AN:

1461700

Hom.:

Cov.:

AF XY:

0.000748

AC XY:

544

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.0274

AC:

917

AN:

33474

American (AMR)

AF:

0.00145

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.000869

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

1112010

Other (OTH)

AF:

0.00185

AC:

112

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00751

AC:

1144

AN:

152304

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0262

AC:

1087

AN:

41562

American (AMR)

AF:

0.00235

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000579

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68028

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00444

Hom.:

Bravo

AF:

0.00864

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Developmental and epileptic encephalopathy, 5 (2)

Developmental and epileptic encephalopathy (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.99

(source)

DANN

Benign

0.62

PhyloP100

-0.52

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over