19-40523602-G-T

Position:

• chr19-40523602-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_020971.3(SPTBN4):​c.3820G>T​(p.Glu1274*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,624 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTBN4 NM_020971.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.73

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 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 19-40523602-G-T is Pathogenic according to our data. Variant chr19-40523602-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 559545.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-40523602-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN4	NM_020971.3	c.3820G>T	p.Glu1274*	stop_gained	17/36	ENST00000598249.6	NP_066022.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6	c.3820G>T	p.Glu1274*	stop_gained	17/36	1	NM_020971.3	ENSP00000469242.1
SPTBN4	ENST00000352632.7	c.3820G>T	p.Glu1274*	stop_gained	17/36	5		ENSP00000263373.2
SPTBN4	ENST00000595535.5	c.3820G>T	p.Glu1274*	stop_gained	17/27	5		ENSP00000470693.1
SPTBN4	ENST00000597389.5	n.1996G>T		non_coding_transcript_exon_variant	4/24	5		ENSP00000472136.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727092

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

The E1274X variant in the SPTBN4 gene has been reported previously in the homozygous state in multiple affected individuals from the same family with congenital hypotonia, global developmental delay, cortical visual impairment, and respiratory difficulties (Wang et al., 2018). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay, and published functional studies confirmed that E1274X disrupts spectrin protein function (Wang et al., 2018). The E1274X variant is not observed in large population cohorts (Lek et al., 2016). We interpret E1274X as a pathogenic variant. -

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	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.29
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: rs1555818396; hg19: chr19-41029509;