rs770046688
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_001130438.3(SPTAN1):c.1806+4A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,612,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000043 ( 0 hom. )
Consequence
SPTAN1
NM_001130438.3 splice_donor_region, intron
NM_001130438.3 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9952
2
Clinical Significance
Conservation
PhyloP100: 2.85
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant 9-128582853-A-G is Benign according to our data. Variant chr9-128582853-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207265.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2, Benign=1}.
BS2
?
High AC in GnomAd at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPTAN1 | NM_001130438.3 | c.1806+4A>G | splice_donor_region_variant, intron_variant | ENST00000372739.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPTAN1 | ENST00000372739.7 | c.1806+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_001130438.3 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152218Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000231 AC: 58AN: 250568Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135508
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GnomAD4 exome AF: 0.0000431 AC: 63AN: 1460056Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20AN XY: 726380
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Developmental and epileptic encephalopathy, 5 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Apr 26, 2020 | The inherited c.1806+4A>G splice-region variant is located in intron14 (of 56) of the SPTAN1 gene and is predicted by multiple In Silico tools to alter normal mRNA splicing. This variant has not been reported in the affected individuals in the literature. The variant has been reported in ClinVar (Variation ID: 207265). The variant has 0.0002315 allele frequency in the gnomAD database across all populations (58 out of 250,568 heterozygous alleles) and 0.00159 allele frequency in Latino subpopulation represented in gnomAD (55 out of 34,578 heterozygous alleles). The c.1806+4A>G variant affects a moderately conserved nucleotide. Functional studies are required to evaluate the potential pathogenicity of this variant. Based on the available evidence, the inherited c.1806+4A>G splice-region variant in the SPTAN1 gene is assessed as a variant of uncertain significance. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Aug 31, 2021 | SPTAN1 NM_001130438.2 intron 14 c.1806+4A>G: This variant has not been reported in the literature but is present in 0.2% (55/34578) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/9-131345132-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:207265). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Splice prediction tools suggest that this variant may alter splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 09, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2020 | - - |
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at