Variant 19-40570712-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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 Lovd as [Pathogenic].

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SPTBN4	NM_020971.3 linkuse as main transcript	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	ENST00000598249.6	NP_066022.2
SPTBN4	XM_017027049.2 linkuse as main transcript	c.7303C>A	p.Arg2435Ser	missense_variant	33/36		XP_016882538.1
SPTBN4	XM_017027050.2 linkuse as main transcript	c.6961C>A	p.Arg2321Ser	missense_variant	31/34		XP_016882539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTBN4	ENST00000598249.6 linkuse as main transcript	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	1	NM_020971.3	ENSP00000469242	P1	Q9H254-1
SPTBN4	ENST00000352632.7 linkuse as main transcript	c.7303C>A	p.Arg2435Ser	missense_variant	33/36	5		ENSP00000263373	P1	Q9H254-1
SPTBN4	ENST00000597389.5 linkuse as main transcript	c.*3459C>A		3_prime_UTR_variant, NMD_transcript_variant	21/24	5		ENSP00000472136

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000872

AC:

AN:

229398

Hom.:

AF XY:

0.00000789

AC XY:

AN XY:

126782

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 SAS exome

AF:

0.0000336

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

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:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

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

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;.

MutationTaster

Benign

0.65

D;D

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

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over