rs3750333

chr9-128617719-C-Achr9-128617719-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001130438.3(SPTAN1):c.5437C>A(p.Arg1813=) 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:7
• Conservation: PhyloP100: 3.99

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 160017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-128617719-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.5437C>A	p.Arg1813=	synonymous_variant	42/57	ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.5437C>A	p.Arg1813=	synonymous_variant	42/57	1	NM_001130438.3	P3

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

GnomAD3 exomes AF: 0.0247 AC: 6195 AN: 251294 Hom.: 132 AF XY: 0.0233 AC XY: 3170 AN XY: 135844

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 SAS exome AF: 0.0243

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

Gnomad4 AFR exome AF: 0.00332

Gnomad4 AMR exome AF: 0.0507

Gnomad4 ASJ exome AF: 0.00631

Gnomad4 EAS exome AF: 0.0902

Gnomad4 SAS exome AF: 0.0234

Gnomad4 FIN exome AF: 0.00594

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.0199

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

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0419

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0804

Gnomad4 SAS AF: 0.0245

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0160 Hom.: 43

Bravo AF: 0.0191

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.0168

EpiControl AF: 0.0169

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 04, 2018	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Developmental and epileptic encephalopathy, 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	12
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs3750333; hg19: chr9-131379998; COSMIC: COSV63986751; COSMIC: COSV63986751;