14-64803673-G-T

Position:

• chr14-64803673-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001355436.2(SPTB):​c.408C>A​(p.His136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H136H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.14

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.408C>A	p.His136Gln	missense_variant	4/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.408C>A	p.His136Gln	missense_variant	4/36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000389722.7	c.408C>A	p.His136Gln	missense_variant	3/35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.408C>A	p.His136Gln	missense_variant	4/32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251388 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	.;.;.;D;D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.89	.;.;D;.;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	0.88	L;L;L;L;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.5	D;.;D;D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Uncertain	0.0020	D;.;D;D;D
Polyphen		1.0	.;.;.;D;D
Vest4		0.70
MutPred		0.45		Loss of catalytic residue at D137 (P = 0.1213);Loss of catalytic residue at D137 (P = 0.1213);Loss of catalytic residue at D137 (P = 0.1213);Loss of catalytic residue at D137 (P = 0.1213);Loss of catalytic residue at D137 (P = 0.1213);
MVP		0.95
MPC		1.7
ClinPred		0.83	D
GERP RS		-3.8
Varity_R		0.87
gMVP		0.46

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: rs11623956; hg19: chr14-65270391;