rs147235045

chr14-64786950-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001355436.2(SPTB):c.3015C>T(p.Ala1005=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,613,784 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: -8.92

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-64786950-G-A is Benign according to our data. Variant chr14-64786950-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257107.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-8.92 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.3015C>T	p.Ala1005=	synonymous_variant	16/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.3015C>T	p.Ala1005=	synonymous_variant	16/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.3015C>T	p.Ala1005=	synonymous_variant	15/35	2		P1
SPTB	ENST00000389720.4	c.3015C>T	p.Ala1005=	synonymous_variant	16/32	5

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00129 AC: 324 AN: 251132 Hom.: 0 AF XY: 0.00144 AC XY: 195 AN XY: 135798

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00158 AC: 2305 AN: 1461538 Hom.: 5 Cov.: 35 AF XY: 0.00163 AC XY: 1183 AN XY: 727102

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00319

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74454

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00125 Hom.: 0

Bravo AF: 0.00116

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SPTB: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 27, 2023	- -

Elliptocytosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.52
Dann	Benign	0.75
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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: rs147235045; hg19: chr14-65253668;