19-40570712-C-T

Position:

chr19-40570712-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_020971.3(SPTBN4):c.7303C>T(p.Arg2435Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,608,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

SPTBN4
NM_020971.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

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;

PP5

Variant 19-40570712-C-T is Pathogenic according to our data. Variant chr19-40570712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 559548.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-40570712-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.0737026). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTBN4	NM_020971.3 linkuse as main transcript	c.7303C>T	p.Arg2435Cys	missense_variant	33/36	ENST00000598249.6	NP_066022.2	Q9H254-1
SPTBN4	XM_017027049.2 linkuse as main transcript	c.7303C>T	p.Arg2435Cys	missense_variant	33/36		XP_016882538.1	Q9H254-1
SPTBN4	XM_017027050.2 linkuse as main transcript	c.6961C>T	p.Arg2321Cys	missense_variant	31/34		XP_016882539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPTBN4	ENST00000598249.6 linkuse as main transcript	c.7303C>T	p.Arg2435Cys	missense_variant	33/36	1	NM_020971.3	ENSP00000469242.1	Q9H254-1
SPTBN4	ENST00000352632.7 linkuse as main transcript	c.7303C>T	p.Arg2435Cys	missense_variant	33/36	5		ENSP00000263373.2	Q9H254-1
SPTBN4	ENST00000597389.5 linkuse as main transcript	n.*3459C>T		non_coding_transcript_exon_variant	21/24	5		ENSP00000472136.1	M0R1V6
SPTBN4	ENST00000597389.5 linkuse as main transcript	n.*3459C>T		3_prime_UTR_variant	21/24	5		ENSP00000472136.1	M0R1V6

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000100

AC:

AN:

229398

Hom.:

AF XY:

0.0000394

AC XY:

AN XY:

126782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000620

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:

0.0000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1456000

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000428

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000924

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

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

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;D;D;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.89

.;.;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.074

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

.;L;L;.

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-3.8

.;D;.;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

.;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.034

.;B;B;.

Vest4

0.42

MutPred

0.49

Loss of MoRF binding (P = 0.0198);Loss of MoRF binding (P = 0.0198);Loss of MoRF binding (P = 0.0198);Loss of MoRF binding (P = 0.0198);

MVP

0.39

ClinPred

0.28

GERP RS

3.6

Varity_R

0.44

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over