19-40472737-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020971.3(SPTBN4):c.116C>T(p.Ala39Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00283 in 1,606,964 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0029 ( 10 hom. )

Consequence

SPTBN4
NM_020971.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 3.39

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076540112).

BP6

Variant 19-40472737-C-T is Benign according to our data. Variant chr19-40472737-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 770657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00227 (346/152130) while in subpopulation AMR AF= 0.00354 (54/15254). AF 95% confidence interval is 0.00312. There are 1 homozygotes in gnomad4. There are 141 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTBN4	NM_020971.3 link	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 36	ENST00000598249.6	NP_066022.2	Q9H254-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SPTBN4	ENST00000598249.6 link	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 36	1	NM_020971.3	ENSP00000469242.1	Q9H254-1
SPTBN4	ENST00000352632.7 link	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 36	5		ENSP00000263373.2	Q9H254-1
SPTBN4	ENST00000595535.5 link	c.116C>T	p.Ala39Val	missense_variant	Exon 2 of 27	5		ENSP00000470693.1	M0QZQ3

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

345

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00354

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.00384

GnomAD3 exomes

AF:

0.00267

AC:

625

AN:

234124

Hom.:

AF XY:

0.00264

AC XY:

337

AN XY:

127512

show subpopulations

Gnomad AFR exome

AF:

0.000341

Gnomad AMR exome

AF:

0.00427

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00202

Gnomad FIN exome

AF:

0.000690

Gnomad NFE exome

AF:

0.00345

Gnomad OTH exome

AF:

0.00450

GnomAD4 exome

AF:

0.00289

AC:

4199

AN:

1454834

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2062

AN XY:

723282

show subpopulations

Gnomad4 AFR exome

AF:

0.000479

Gnomad4 AMR exome

AF:

0.00430

Gnomad4 ASJ exome

AF:

0.00224

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00185

Gnomad4 FIN exome

AF:

0.000818

Gnomad4 NFE exome

AF:

0.00315

Gnomad4 OTH exome

AF:

0.00322

GnomAD4 genome

AF:

0.00227

AC:

346

AN:

152130

Hom.:

Cov.:

AF XY:

0.00190

AC XY:

141

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.00354

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00349

Gnomad4 OTH

AF:

0.00380

Alfa

AF:

0.00277

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00248

AC:

301

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPTBN4: PP2, BP4, BS2 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SPTBN4-related disorder

Benign:1

Apr 28, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

.;T;T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.74

T;.;.;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.0077

T;T;T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

1.1

.;.;L;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.78

.;.;N;.;N

REVEL

Benign

0.28

Sift

Benign

0.044

.;.;D;.;D

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.67

.;.;P;P;.

Vest4

0.38

MVP

0.71

ClinPred

0.032

GERP RS

6.0

Varity_R

0.11

gMVP

0.25

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over