rs1555369657

Positions:

• chr14-64787102-G-A

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.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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.754

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 14-64787102-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
SPTB	NM_001355436.2	c.2863C>T	p.Arg955Ter	stop_gained	16/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.2863C>T	p.Arg955Ter	stop_gained	16/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.2863C>T	p.Arg955Ter	stop_gained	15/35	2		P1
SPTB	ENST00000389720.4	c.2863C>T	p.Arg955Ter	stop_gained	16/32	5

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

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

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	ClinVar 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). -

Hereditary spherocytosis type 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris	Feb 27, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics 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

Other links and lift over

dbSNP: rs1555369657; hg19: chr14-65253820;