rs229581

Positions:

• chr14-64804932-A-G
• chr14-64804932-A-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.300+7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.344 in 1,613,542 control chromosomes in the GnomAD database, including 101,038 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 0.42 (14818 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86220 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003127
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.457

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=-0.91).
• BP6: Variant 14-64804932-A-G is Benign according to our data. Variant chr14-64804932-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64804932-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.300+7T>C		splice_region_variant, intron_variant		ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.300+7T>C		splice_region_variant, intron_variant			NM_001355436.2	P1
SPTB	ENST00000389720.4	c.300+7T>C		splice_region_variant, intron_variant		5
SPTB	ENST00000389722.7	c.300+7T>C		splice_region_variant, intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63420 AN: 151970 Hom.: 14792 Cov.: 32

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.413

GnomAD3 exomes AF: 0.359 AC: 89866 AN: 250250 Hom.: 17324 AF XY: 0.363 AC XY: 49126 AN XY: 135400

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.325

Gnomad SAS exome AF: 0.481

Gnomad FIN exome AF: 0.314

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.336 AC: 490788 AN: 1461454 Hom.: 86220 Cov.: 46 AF XY: 0.341 AC XY: 247739 AN XY: 727052

Gnomad4 AFR exome AF: 0.650

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.395

Gnomad4 EAS exome AF: 0.336

Gnomad4 SAS exome AF: 0.476

Gnomad4 FIN exome AF: 0.315

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.417 AC: 63488 AN: 152088 Hom.: 14818 Cov.: 32 AF XY: 0.416 AC XY: 30947 AN XY: 74352

Gnomad4 AFR AF: 0.637

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.351

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.320

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.413

Alfa AF: 0.364 Hom.: 4773

Bravo AF: 0.424

Asia WGS AF: 0.446 AC: 1551 AN: 3478

EpiCase AF: 0.337

EpiControl AF: 0.338

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

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	-0.91
CADD	Benign	6.8
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.090		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: rs229581; hg19: chr14-65271650;