rs945831

chr9-128600082-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001130438.3(SPTAN1):c.3546T>C(p.Asp1182=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,614,158 control chromosomes in the GnomAD database, including 474 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (248 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (226 hom.)
• Consequence: SPTAN1 NM_001130438.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.99

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-128600082-T-C is Benign according to our data. Variant chr9-128600082-T-C is described in ClinVar as [Benign]. Clinvar id is 160010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTAN1	NM_001130438.3	c.3546T>C	p.Asp1182=	splice_region_variant, synonymous_variant	27/57	ENST00000372739.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTAN1	ENST00000372739.7	c.3546T>C	p.Asp1182=	splice_region_variant, synonymous_variant	27/57	1	NM_001130438.3	P3

Frequencies

GnomAD3 genomes AF: 0.0311 AC: 4733 AN: 152182 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00850 AC: 2138 AN: 251490 Hom.: 102 AF XY: 0.00617 AC XY: 838 AN XY: 135920

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00342 AC: 4995 AN: 1461858 Hom.: 226 Cov.: 30 AF XY: 0.00297 AC XY: 2161 AN XY: 727226

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00682

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.00697

GnomAD4 genome AF: 0.0312 AC: 4749 AN: 152300 Hom.: 248 Cov.: 32 AF XY: 0.0300 AC XY: 2238 AN XY: 74484

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.00908 Hom.: 67

Bravo AF: 0.0351

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:6

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	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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	Benign	-0.37
Cadd	Benign	11
Dann	Benign	0.87
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: rs945831; hg19: chr9-131362361; COSMIC: COSV63988933; COSMIC: COSV63988933;