rs4902312

Positions:

• chr14-64775407-C-T

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.4564-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,609,878 control chromosomes in the GnomAD database, including 4,553 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 0.058 (294 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4259 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002860
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.71

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=-0.78).
• BP6: Variant 14-64775407-C-T is Benign according to our data. Variant chr14-64775407-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64775407-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.4564-4G>A		splice_region_variant, intron_variant		ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.4564-4G>A		splice_region_variant, intron_variant			NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.559-4G>A		splice_region_variant, intron_variant		1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.4564-4G>A		splice_region_variant, intron_variant		2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.4564-4G>A		splice_region_variant, intron_variant		5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 8775 AN: 152202 Hom.: 294 Cov.: 33

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0597 AC: 14713 AN: 246310 Hom.: 554 AF XY: 0.0602 AC XY: 8042 AN XY: 133662

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0260

Gnomad SAS exome AF: 0.0302

Gnomad FIN exome AF: 0.0754

Gnomad NFE exome AF: 0.0836

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0729 AC: 106225 AN: 1457558 Hom.: 4259 Cov.: 35 AF XY: 0.0720 AC XY: 52121 AN XY: 724344

Gnomad4 AFR exome AF: 0.0158

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.0517

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.0302

Gnomad4 FIN exome AF: 0.0783

Gnomad4 NFE exome AF: 0.0819

Gnomad4 OTH exome AF: 0.0658

GnomAD4 genome AF: 0.0576 AC: 8777 AN: 152320 Hom.: 294 Cov.: 33 AF XY: 0.0576 AC XY: 4294 AN XY: 74494

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.0532

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.0200

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0769

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0712 Hom.: 250

Bravo AF: 0.0534

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0760

EpiControl AF: 0.0760

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2019	This variant is associated with the following publications: (PMID: 25525159, 19538529, 27884173, 27354418) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.34
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
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: rs4902312; hg19: chr14-65242125;