rs121918649

Variant names:

• chr14-64767808-A-C
• rs121918649
• NM_001355436.2:c.6074T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001355436.2(SPTB):​c.6074T>G​(p.Leu2025Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 9.28

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• PP5: Variant 14-64767808-A-C is Pathogenic according to our data. Variant chr14-64767808-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 12839.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6074T>G	p.Leu2025Arg	missense_variant	Exon 30 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.6074T>G	p.Leu2025Arg	missense_variant	Exon 30 of 36		NM_001355436.2	ENSP00000495909.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

ANEMIA, PERINATAL HEMOLYTIC, FATAL OR NEAR-FATAL Pathogenic:1

Mar 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

SPTB-related disorder Pathogenic:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPTB c.6074T>G variant is predicted to result in the amino acid substitution p.Leu2025Arg. This variant is also known as spectrin Buffalo and has been noted to be common in individuals with hemolytic anemia in the Thai population (Songdej et al. 2024. PubMed ID: 35819869). It has been reported in the homozygous or compound heterozygous states in individuals with severe inherited hemolytic anemia (Gallagher et al. 1997. PubMed ID: 9005995; Ittiwut et al. 2018. PubMed ID: 30198572; Songdej et al. 2024. PubMed ID: 37996759). Individuals heterozygous for this variant have been reported to have a milder elliptocytosis phenotype (Gallagher et al. 1997. PubMed ID: 9005995; Songdej et al. 2024. PubMed ID: 37996759). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted to be pathogenic. -

not provided Pathogenic:1

Jan 26, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spherocytosis type 2 Uncertain:1

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous p.Leu2025Arg variant in SPTB was identified by our study in one individual with spherocytosis. This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu2025Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;.;.;T;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D;D;.;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Pathogenic	3.6	H;H;H;.;H;H
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.5	D;.;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;D;D;D;D
Sift4G	Pathogenic	0.0	D;.;D;D;D;D
Polyphen		1.0	.;.;.;.;D;D
Vest4		0.99
MutPred		0.60		Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);.;Gain of MoRF binding (P = 0.0682);Gain of MoRF binding (P = 0.0682);
MVP		0.83
MPC		0.93
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.98
gMVP		0.84

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: rs121918649; hg19: chr14-65234526; COSMIC: COSV61552372; COSMIC: COSV61552372;