rs121918647

chr14-64767829-G-Cchr14-64767829-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_001355436.2(SPTB):c.6053C>G(p.Ala2018Gly) 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2018D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.96

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001355436.2
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.757
• PP5: Variant 14-64767829-G-C is Pathogenic according to our data. Variant chr14-64767829-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12836.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.6053C>G	p.Ala2018Gly	missense_variant	30/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.6053C>G	p.Ala2018Gly	missense_variant	30/36		NM_001355436.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Elliptocytosis 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 25, 1993

- -

Pyropoikilocytosis, hereditary Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 25, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Pathogenic	3.3	M;M;M;.;M;M
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.7	D;.;D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0030	D;.;D;D;D;D
Sift4G	Uncertain	0.0030	D;.;D;D;D;D
Polyphen		0.14	.;.;.;.;B;B
Vest4		0.56
MutPred		0.45		Gain of catalytic residue at A2018 (P = 0.0534);Gain of catalytic residue at A2018 (P = 0.0534);Gain of catalytic residue at A2018 (P = 0.0534);.;Gain of catalytic residue at A2018 (P = 0.0534);Gain of catalytic residue at A2018 (P = 0.0534);
MVP		0.61
MPC		0.21
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.90
gMVP		0.42

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: rs121918647; hg19: chr14-65234547;