chr14-64750117-C-A

Variant names:

• chr14-64750117-C-A
• NM_001355436.2:c.6640G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001355436.2(SPTB):​c.6640G>T​(p.Glu2214*) variant causes a stop gained change involving the alteration of a non-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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPTB NM_001355436.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.12

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]

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 14-64750117-C-A is Pathogenic according to our data. Variant chr14-64750117-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 3772398.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6640G>T	p.Glu2214*	stop_gained	Exon 34 of 36	ENST00000644917.1	NP_001342365.1
PLEKHG3	NM_001308147.2	c.*6414C>A		3_prime_UTR_variant	Exon 17 of 17	ENST00000247226.13	NP_001295076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.6640G>T	p.Glu2214*	stop_gained	Exon 34 of 36		NM_001355436.2	ENSP00000495909.1
PLEKHG3	ENST00000247226.13	c.*6414C>A		3_prime_UTR_variant	Exon 17 of 17	1	NM_001308147.2	ENSP00000247226.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPTB: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.29	N
Vest4		0.76
GERP RS		3.4

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-65216835;