14-64750020-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001355436.2(SPTB):c.6737C>T(p.Ala2246Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41911787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.6737C>T	p.Ala2246Val	missense_variant	34/36	ENST00000644917.1
PLEKHG3	NM_001308147.2	c.*6317G>A		3_prime_UTR_variant	17/17	ENST00000247226.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.6737C>T	p.Ala2246Val	missense_variant	34/36		NM_001355436.2	P1
PLEKHG3	ENST00000247226.13	c.*6317G>A		3_prime_UTR_variant	17/17	1	NM_001308147.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hemolytic anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 27, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Uncertain	25
Dann	Pathogenic	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationTaster	Benign	0.91	N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.4	N;.;N;N
REVEL	Benign	0.23
Sift	Benign	0.042	D;.;D;D
Sift4G	Uncertain	0.050	T;.;T;T
Vest4		0.67
MutPred		0.69		Gain of methylation at K2251 (P = 0.0786);Gain of methylation at K2251 (P = 0.0786);Gain of methylation at K2251 (P = 0.0786);.;
MVP		0.25
MPC		0.69
ClinPred		0.94	D
GERP RS		4.6
gMVP		0.59

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: rs1555364743; hg19: chr14-65216738;