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rs1555369657

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001355436.2(SPTB):c.2863C>T(p.Arg955Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SPTB
NM_001355436.2 stop_gained

Scores

2
2
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.754
Variant links:
Genes affected
SPTB (HGNC:11274): (spectrin beta, erythrocytic) This locus encodes a member of the spectrin gene family. Spectrin proteins, along with ankyrin, play a role in cell membrane organization and stability. The protein encoded by this locus functions in stability of erythrocyte membranes, and mutations in this gene have been associated with spherocytosis type 2, hereditary elliptocytosis, and neonatal hemolytic anemia. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-64787102-G-A is Pathogenic according to our data. Variant chr14-64787102-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 544812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SPTBNM_001355436.2 linkuse as main transcriptc.2863C>T p.Arg955Ter stop_gained 16/36 ENST00000644917.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SPTBENST00000644917.1 linkuse as main transcriptc.2863C>T p.Arg955Ter stop_gained 16/36 NM_001355436.2 P1P11277-2
SPTBENST00000389722.7 linkuse as main transcriptc.2863C>T p.Arg955Ter stop_gained 15/352 P1P11277-2
SPTBENST00000389720.4 linkuse as main transcriptc.2863C>T p.Arg955Ter stop_gained 16/325 P11277-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1457162
Hom.:
0
Cov.:
35
AF XY:
0.00000138
AC XY:
1
AN XY:
725200
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 17, 2023ClinVar contains an entry for this variant (Variation ID: 544812). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal dominant SPTB-related conditions (PMID: 29572776, 31602632, 32641076). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg955*) in the SPTB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPTB are known to be pathogenic (PMID: 1391962, 1498324, 8844207, 26830532, 27292444). -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 03, 2023- -
Hereditary spherocytosis type 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingDepartment of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de ParisFeb 27, 2018- -
Likely pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
Cadd
Pathogenic
47
Dann
Uncertain
1.0
Eigen
Uncertain
0.37
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.33
N
MutationTaster
Benign
1.0
A;A;A;A;A
Vest4
0.96
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs1555369657; hg19: chr14-65253820; API