chr19-40472721-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020971.3(SPTBN4):​c.100C>T​(p.Arg34Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SPTBN4
NM_020971.3 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.11
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]

Genome browser will be placed here

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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPTBN4NM_020971.3 linkc.100C>T p.Arg34Trp missense_variant Exon 2 of 36 ENST00000598249.6 NP_066022.2 Q9H254-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPTBN4ENST00000598249.6 linkc.100C>T p.Arg34Trp missense_variant Exon 2 of 36 1 NM_020971.3 ENSP00000469242.1 Q9H254-1
SPTBN4ENST00000352632.7 linkc.100C>T p.Arg34Trp missense_variant Exon 2 of 36 5 ENSP00000263373.2 Q9H254-1
SPTBN4ENST00000595535.5 linkc.100C>T p.Arg34Trp missense_variant Exon 2 of 27 5 ENSP00000470693.1 M0QZQ3

Frequencies

GnomAD3 genomes
AF:
0.0000724
AC:
11
AN:
151892
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000967
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000209
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000836
AC:
2
AN:
239288
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
130388
show subpopulations
Gnomad AFR exome
AF:
0.000134
Gnomad AMR exome
AF:
0.00
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1456818
Hom.:
0
Cov.:
30
AF XY:
0.00000690
AC XY:
5
AN XY:
724442
show subpopulations
Gnomad4 AFR exome
AF:
0.0000898
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000901
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000724
AC:
11
AN:
151892
Hom.:
0
Cov.:
32
AF XY:
0.0000539
AC XY:
4
AN XY:
74164
show subpopulations
Gnomad4 AFR
AF:
0.0000967
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000209
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000658
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 10, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.100C>T (p.R34W) alteration is located in exon 2 (coding exon 1) of the SPTBN4 gene. This alteration results from a C to T substitution at nucleotide position 100, causing the arginine (R) at amino acid position 34 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Benign
-0.048
T
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.022
.;T;T;T;T
Eigen
Benign
0.11
Eigen_PC
Benign
0.18
FATHMM_MKL
Benign
0.62
D
LIST_S2
Uncertain
0.88
D;.;.;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.71
D;D;D;D;D
MetaSVM
Uncertain
-0.18
T
MutationAssessor
Benign
0.69
.;.;N;N;.
PrimateAI
Uncertain
0.61
T
PROVEAN
Benign
-1.6
.;.;N;.;N
REVEL
Uncertain
0.54
Sift
Uncertain
0.0060
.;.;D;.;D
Sift4G
Uncertain
0.016
D;D;D;D;D
Polyphen
1.0
.;.;D;D;.
Vest4
0.70
MVP
0.76
ClinPred
0.45
T
GERP RS
4.0
Varity_R
0.087
gMVP
0.50

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.

Other links and lift over

dbSNP: rs372051643; hg19: chr19-40978628; COSMIC: COSV58957920; API