rs864309618

Variant names:

• chr19-40513498-G-A
• rs864309618
• NM_020971.3:c.2709G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_020971.3(SPTBN4):​c.2709G>A​(p.Trp903*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTBN4 NM_020971.3 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 9.68
• Publications: 0 publications found

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]

SPTBN4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with hypotonia, neuropathy, and deafness

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 10 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020971.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN4	NM_020971.3	MANE Select	c.2709G>A	p.Trp903*	stop_gained	Exon 14 of 36	NP_066022.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTBN4	ENST00000598249.6	TSL:1 MANE Select	c.2709G>A	p.Trp903*	stop_gained	Exon 14 of 36	ENSP00000469242.1
	SPTBN4	ENST00000352632.7	TSL:5	c.2709G>A	p.Trp903*	stop_gained	Exon 14 of 36	ENSP00000263373.2
	SPTBN4	ENST00000595535.5	TSL:5	c.2709G>A	p.Trp903*	stop_gained	Exon 14 of 27	ENSP00000470693.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 231804 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Neurodevelopmental disorder with hypotonia, neuropathy, and deafness (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.7
Vest4		0.38
GERP RS		3.3
Mutation Taster		=0/200	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs864309618; hg19: chr19-41019405;