rs1626923

Positions:

• chr14-64779905-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.4293A>G​(p.Arg1431=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,268 control chromosomes in the GnomAD database, including 96,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (13942 hom., cov: 31)
  • Exomes 𝑓: 0.33 (82794 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.31

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-64779905-T-C is Benign according to our data. Variant chr14-64779905-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64779905-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4293A>G	p.Arg1431=	synonymous_variant	21/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4293A>G	p.Arg1431=	synonymous_variant	21/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.288A>G	p.Arg96=	synonymous_variant	2/18	1
SPTB	ENST00000389722.7	c.4293A>G	p.Arg1431=	synonymous_variant	20/35	2		P1
SPTB	ENST00000389720.4	c.4293A>G	p.Arg1431=	synonymous_variant	21/32	5

Frequencies

GnomAD3 genomes AF: 0.402 AC: 61031 AN: 151840 Hom.: 13911 Cov.: 31

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.297

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.330

Gnomad EAS AF: 0.364

Gnomad SAS AF: 0.412

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.373

GnomAD3 exomes AF: 0.336 AC: 84212 AN: 250516 Hom.: 15509 AF XY: 0.339 AC XY: 45864 AN XY: 135434

Gnomad AFR exome AF: 0.638

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.327

Gnomad EAS exome AF: 0.364

Gnomad SAS exome AF: 0.409

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.328

GnomAD4 exome AF: 0.330 AC: 482373 AN: 1461310 Hom.: 82794 Cov.: 45 AF XY: 0.332 AC XY: 241371 AN XY: 726948

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.332

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.296

Gnomad4 NFE exome AF: 0.320

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.402 AC: 61106 AN: 151958 Hom.: 13942 Cov.: 31 AF XY: 0.400 AC XY: 29677 AN XY: 74252

Gnomad4 AFR AF: 0.630

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.330

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.374

Alfa AF: 0.337 Hom.: 15595

Bravo AF: 0.406

Asia WGS AF: 0.418 AC: 1456 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.326

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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

- -

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	-0.55
CADD	Benign	8.4
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1626923; hg19: chr14-65246623; COSMIC: COSV67633848;