rs777273785

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2PM5BP4_Moderate

The NM_020971.3(SPTBN4):c.7303C>A(p.Arg2435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2435C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SPTBN4
NM_020971.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.64

Publications

2 publications found

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]

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

SPTBN4 links:

ENSG00000301397 (HGNC:):

ENSG00000301397 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-40570712-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 559548.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.15354326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN4	NM_020971.3 link	c.7303C>A	p.Arg2435Ser	missense_variant	Exon 33 of 36	ENST00000598249.6	NP_066022.2	Q9H254-1
SPTBN4	XM_017027049.2 link	c.7303C>A	p.Arg2435Ser	missense_variant	Exon 33 of 36		XP_016882538.1	Q9H254-1
SPTBN4	XM_017027050.2 link	c.6961C>A	p.Arg2321Ser	missense_variant	Exon 31 of 34		XP_016882539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6 link	c.7303C>A	p.Arg2435Ser	missense_variant	Exon 33 of 36	1	NM_020971.3	ENSP00000469242.1		Q9H254-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000872

AC:

AN:

229398

AF XY:

0.00000789

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

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

AF:

0.00000137

AC:

AN:

1456000

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39118

South Asian (SAS)

AF:

0.0000233

AC:

AN:

85754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109982

Other (OTH)

AF:

0.00

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000168

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

T;T;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.78

.;.;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;L;.

PhyloP100

1.6

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

.;N;.;.

REVEL

Benign

0.22

Sift

Uncertain

0.0010

.;D;.;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.68

.;P;P;.

Vest4

0.31

MutPred

0.47

Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);

MVP

0.43

ClinPred

0.72

GERP RS

3.6

Varity_R

0.39

gMVP

0.46

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over