rs56181906

Positions:

• chr14-64767867-G-A

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.6023-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,613,082 control chromosomes in the GnomAD database, including 13,277 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 0.17 (2991 hom., cov: 32)
  • Exomes 𝑓: 0.11 (10286 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.001358
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00800

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]

SPTB (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 14-64767867-G-A is Benign according to our data. Variant chr14-64767867-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64767867-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6023-8C>T		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.6023-8C>T		splice_region_variant, intron_variant			NM_001355436.2	ENSP00000495909.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25226 AN: 151934 Hom.: 2984 Cov.: 32

Gnomad AFR AF: 0.338

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.00714

Gnomad SAS AF: 0.0634

Gnomad FIN AF: 0.0789

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.142

GnomAD3 exomes AF: 0.105 AC: 26205 AN: 249694 Hom.: 2030 AF XY: 0.101 AC XY: 13609 AN XY: 135048

Gnomad AFR exome AF: 0.345

Gnomad AMR exome AF: 0.0656

Gnomad ASJ exome AF: 0.0929

Gnomad EAS exome AF: 0.00921

Gnomad SAS exome AF: 0.0699

Gnomad FIN exome AF: 0.0825

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.109 AC: 159793 AN: 1461030 Hom.: 10286 Cov.: 32 AF XY: 0.108 AC XY: 78179 AN XY: 726790

Gnomad4 AFR exome AF: 0.345

Gnomad4 AMR exome AF: 0.0708

Gnomad4 ASJ exome AF: 0.0990

Gnomad4 EAS exome AF: 0.00562

Gnomad4 SAS exome AF: 0.0688

Gnomad4 FIN exome AF: 0.0858

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.166 AC: 25262 AN: 152052 Hom.: 2991 Cov.: 32 AF XY: 0.161 AC XY: 12003 AN XY: 74324

Gnomad4 AFR AF: 0.338

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.00696

Gnomad4 SAS AF: 0.0628

Gnomad4 FIN AF: 0.0789

Gnomad4 NFE AF: 0.114

Gnomad4 OTH AF: 0.141

Alfa AF: 0.140 Hom.: 862

Bravo AF: 0.173

Asia WGS AF: 0.0640 AC: 225 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 29, 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	-0.66
CADD	Benign	2.5
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.052
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: rs56181906; hg19: chr14-65234585;