rs1555721549

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_020971.3(SPTBN4):​c.7453delG​(p.Ala2485fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

SPTBN4
NM_020971.3 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 0.526
Variant links:
Genes affected
SPTBN4 (HGNC:14896): (spectrin beta, non-erythrocytic 4) Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. It is composed of two antiparallel dimers of alpha- and beta- subunits. This gene is one member of a family of beta-spectrin genes. The encoded protein localizes to the nuclear matrix, PML nuclear bodies, and cytoplasmic vesicles. A highly similar gene in the mouse is required for localization of specific membrane proteins in polarized regions of neurons. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-40572150-TG-T is Pathogenic according to our data. Variant chr19-40572150-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559549.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-40572150-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPTBN4NM_020971.3 linkc.7453delG p.Ala2485fs frameshift_variant 34/36 ENST00000598249.6 NP_066022.2 Q9H254-1
SPTBN4XM_017027049.2 linkc.7453delG p.Ala2485fs frameshift_variant 34/36 XP_016882538.1 Q9H254-1
SPTBN4XM_017027050.2 linkc.7111delG p.Ala2371fs frameshift_variant 32/34 XP_016882539.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPTBN4ENST00000598249.6 linkc.7453delG p.Ala2485fs frameshift_variant 34/361 NM_020971.3 ENSP00000469242.1 Q9H254-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 05, 2018- -
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 13, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555721549; hg19: chr19-41078056; API