rs150471537

chr14-64784333-G-Achr14-64784333-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001355436.2(SPTB):c.3916C>T(p.Arg1306Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,350 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SPTB NM_001355436.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.99

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]

ACMG classification

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 14-64784333-G-A is Pathogenic according to our data. Variant chr14-64784333-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 544816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.3916C>T	p.Arg1306Ter	stop_gained	19/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.3916C>T	p.Arg1306Ter	stop_gained	19/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.3916C>T	p.Arg1306Ter	stop_gained	18/35	2		P1
SPTB	ENST00000389720.4	c.3916C>T	p.Arg1306Ter	stop_gained	19/32	5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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 Cov.: 33

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74508

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 22, 2022	PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SPTB: PVS1, PS4:Moderate, PM2:Supporting, PM6:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 08, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with clinical features of spherocytosis (PMID: 29572776). This variant is present in population databases (rs150471537, ExAC 0.009%). This sequence change creates a premature translational stop signal (p.Arg1306*) 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: 8844207, 26830532, 27292444). -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 29, 2023	The SPTB c.3916C>T; p.Arg1306Ter variant (rs150471537) is reported in the literature in two individuals affected with hereditary spherocytosis (Mansour-Hendili 2020, Wang 2018). This variant is also reported in ClinVar (Variation ID: 544816). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Mansour-Hendili L et al. Exome sequencing for diagnosis of congenital hemolytic anemia. Orphanet J Rare Dis. 2020 Jul 8. PMID: 32641076 Wang R et al. Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis. Sci China Life Sci. 2018 Aug. PMID: 29572776 -

Hereditary spherocytosis type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris

Feb 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	40
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.90	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.92
GERP RS		3.5

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

Other links and lift over

dbSNP: rs150471537; hg19: chr14-65251051;