rs78707026

Positions:

• chr14-64782565-A-G

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.4003-12T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 1,613,164 control chromosomes in the GnomAD database, including 5,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (334 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4784 hom.)
• Consequence: SPTB NM_001355436.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001462
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.542

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=-0.8).
• BP6: Variant 14-64782565-A-G is Benign according to our data. Variant chr14-64782565-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64782565-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0884 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.4003-12T>C		splice_polypyrimidine_tract_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.4003-12T>C		splice_polypyrimidine_tract_variant, intron_variant			NM_001355436.2	ENSP00000495909	P1
SPTB	ENST00000389720.4	c.4003-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000374370
SPTB	ENST00000389722.7	c.4003-12T>C		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000374372	P1
SPTB	ENST00000553938.5			upstream_gene_variant		1		ENSP00000451324

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9106 AN: 152170 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.0474

GnomAD3 exomes AF: 0.0635 AC: 15582 AN: 245258 Hom.: 615 AF XY: 0.0641 AC XY: 8528 AN XY: 133124

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0442

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.0298

Gnomad SAS exome AF: 0.0322

Gnomad FIN exome AF: 0.0733

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0774 AC: 113010 AN: 1460876 Hom.: 4784 Cov.: 33 AF XY: 0.0766 AC XY: 55701 AN XY: 726750

Gnomad4 AFR exome AF: 0.0119

Gnomad4 AMR exome AF: 0.0468

Gnomad4 ASJ exome AF: 0.0642

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0320

Gnomad4 FIN exome AF: 0.0759

Gnomad4 NFE exome AF: 0.0867

Gnomad4 OTH exome AF: 0.0699

GnomAD4 genome AF: 0.0599 AC: 9116 AN: 152288 Hom.: 334 Cov.: 32 AF XY: 0.0593 AC XY: 4418 AN XY: 74482

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.0562

Gnomad4 ASJ AF: 0.0669

Gnomad4 EAS AF: 0.0256

Gnomad4 SAS AF: 0.0311

Gnomad4 FIN AF: 0.0752

Gnomad4 NFE AF: 0.0903

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0771 Hom.: 116

Bravo AF: 0.0557

Asia WGS AF: 0.0580 AC: 200 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.060		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: rs78707026; hg19: chr14-65249283;