rs230703

Positions:

• chr14-64800751-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.876+5A>G variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 1,612,972 control chromosomes in the GnomAD database, including 84,087 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11223 hom., cov: 33)
  • Exomes 𝑓: 0.31 (72864 hom.)
• Consequence: SPTB NM_001355436.2 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.00007788
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.737

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 14-64800751-T-C is Benign according to our data. Variant chr14-64800751-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64800751-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.876+5A>G		splice_donor_5th_base_variant, intron_variant		ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.876+5A>G		splice_donor_5th_base_variant, intron_variant			NM_001355436.2	P1
SPTB	ENST00000389720.4	c.876+5A>G		splice_donor_5th_base_variant, intron_variant		5
SPTB	ENST00000389722.7	c.876+5A>G		splice_donor_5th_base_variant, intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.366 AC: 55582 AN: 151960 Hom.: 11207 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.363

GnomAD3 exomes AF: 0.316 AC: 79366 AN: 251104 Hom.: 13606 AF XY: 0.322 AC XY: 43674 AN XY: 135706

Gnomad AFR exome AF: 0.539

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.133

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.327

GnomAD4 exome AF: 0.309 AC: 452024 AN: 1460894 Hom.: 72864 Cov.: 33 AF XY: 0.313 AC XY: 227847 AN XY: 726808

Gnomad4 AFR exome AF: 0.541

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.378

Gnomad4 EAS exome AF: 0.162

Gnomad4 SAS exome AF: 0.425

Gnomad4 FIN exome AF: 0.302

Gnomad4 NFE exome AF: 0.299

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.366 AC: 55624 AN: 152078 Hom.: 11223 Cov.: 33 AF XY: 0.364 AC XY: 27064 AN XY: 74328

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.369

Gnomad4 EAS AF: 0.153

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.307

Gnomad4 NFE AF: 0.302

Gnomad4 OTH AF: 0.358

Alfa AF: 0.317 Hom.: 19048

Bravo AF: 0.368

Asia WGS AF: 0.322 AC: 1121 AN: 3478

EpiCase AF: 0.317

EpiControl AF: 0.317

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Elliptocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary spherocytosis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.8
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000078
dbscSNV1_RF	Benign	0.020
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: rs230703; hg19: chr14-65267469; COSMIC: COSV67635994;