rs1114167445

chr19-40504064-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_020971.3(SPTBN4):c.1597C>T(p.Gln533Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPTBN4 NM_020971.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.349

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 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 19-40504064-C-T is Pathogenic according to our data. Variant chr19-40504064-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375254.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTBN4	NM_020971.3	c.1597C>T	p.Gln533Ter	stop_gained	12/36	ENST00000598249.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTBN4	ENST00000598249.6	c.1597C>T	p.Gln533Ter	stop_gained	12/36	1	NM_020971.3	P1
SPTBN4	ENST00000352632.7	c.1597C>T	p.Gln533Ter	stop_gained	12/36	5		P1
SPTBN4	ENST00000595535.5	c.1597C>T	p.Gln533Ter	stop_gained	12/27	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000800 AC: 2 AN: 250040 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Charité Universitätsmedizin Berlin, Charite Universitaetsmedizin Berlin

Jan 03, 2017

Homozygosity for the mutations segregates with the phenotype in the family. The absence of the beta-IV spectrin protein could be verified by immunohistology in muscle and by Western blot in muscle and in fibroblasts of the patients. The patient phenotype largely corresponds to the phenotype of the quivering mouse, which has a mutation in the same gene. -

Neurodevelopmental disorder with hypotonia, neuropathy, and deafness Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.78	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.31
GERP RS		4.3

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: rs1114167445; hg19: chr19-41009971;