NM_001355436.2:c.6863A>C

Variant names:

• chr14-64749430-T-G
• rs765605676
• NM_001355436.2:c.6863A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001355436.2(SPTB):​c.6863A>C​(p.Asn2288Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,604,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09671384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6863A>C	p.Asn2288Thr	missense_variant	Exon 36 of 36	ENST00000644917.1	NP_001342365.1
PLEKHG3	NM_001308147.2	c.*5727T>G		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.6863A>C	p.Asn2288Thr	missense_variant	Exon 36 of 36		NM_001355436.2	ENSP00000495909.1
PLEKHG3	ENST00000247226.13	c.*5727T>G		3_prime_UTR_variant	Exon 17 of 17	1	NM_001308147.2	ENSP00000247226.8

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1452506 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722754

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152144 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.0017	.;.;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.47	.;.;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.097	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.28	N;.;N;N
REVEL	Benign	0.093
Sift	Benign	0.56	T;.;T;T
Sift4G	Benign	0.43	T;.;T;T
Vest4		0.046
MutPred		0.39		Gain of phosphorylation at N2288 (P = 0.0709);Gain of phosphorylation at N2288 (P = 0.0709);Gain of phosphorylation at N2288 (P = 0.0709);.;
MVP		0.093
MPC		0.20
ClinPred		0.80	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.30

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: rs765605676; hg19: chr14-65216148;