rs2277503

chr14-64805062-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):c.177C>T(p.Thr59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0483 in 1,614,128 control chromosomes in the GnomAD database, including 2,448 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (231 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2217 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.46

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 14-64805062-G-A is Benign according to our data. Variant chr14-64805062-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64805062-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.177C>T	p.Thr59=	synonymous_variant	3/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.177C>T	p.Thr59=	synonymous_variant	3/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.177C>T	p.Thr59=	synonymous_variant	2/35	2		P1
SPTB	ENST00000389720.4	c.177C>T	p.Thr59=	synonymous_variant	3/32	5

Frequencies

GnomAD3 genomes AF: 0.0465 AC: 7069 AN: 152120 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0446

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0589

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0459

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0528 AC: 13275 AN: 251452 Hom.: 539 AF XY: 0.0534 AC XY: 7260 AN XY: 135906

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0439

Gnomad EAS exome AF: 0.173

Gnomad SAS exome AF: 0.0573

Gnomad FIN exome AF: 0.0319

Gnomad NFE exome AF: 0.0488

Gnomad OTH exome AF: 0.0463

GnomAD4 exome AF: 0.0485 AC: 70889 AN: 1461890 Hom.: 2217 Cov.: 34 AF XY: 0.0490 AC XY: 35648 AN XY: 727244

Gnomad4 AFR exome AF: 0.0375

Gnomad4 AMR exome AF: 0.0242

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.157

Gnomad4 SAS exome AF: 0.0559

Gnomad4 FIN exome AF: 0.0324

Gnomad4 NFE exome AF: 0.0459

Gnomad4 OTH exome AF: 0.0529

GnomAD4 genome AF: 0.0465 AC: 7075 AN: 152238 Hom.: 231 Cov.: 32 AF XY: 0.0464 AC XY: 3457 AN XY: 74426

Gnomad4 AFR AF: 0.0375

Gnomad4 AMR AF: 0.0340

Gnomad4 ASJ AF: 0.0446

Gnomad4 EAS AF: 0.180

Gnomad4 SAS AF: 0.0587

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.0459

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0475 Hom.: 352

Bravo AF: 0.0471

Asia WGS AF: 0.0900 AC: 314 AN: 3478

EpiCase AF: 0.0483

EpiControl AF: 0.0500

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

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	-0.35
Cadd	Benign	9.2
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2277503; hg19: chr14-65271780; COSMIC: COSV67632090;