rs4902310

chr14-64775188-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.4779A>G(p.Ala1593=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 1,613,904 control chromosomes in the GnomAD database, including 4,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (296 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4305 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -8.17

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=-0.92).
• BP6: Variant 14-64775188-T-C is Benign according to our data. Variant chr14-64775188-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64775188-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-8.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4779A>G	p.Ala1593=	synonymous_variant	23/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4779A>G	p.Ala1593=	synonymous_variant	23/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.774A>G	p.Ala258=	synonymous_variant	4/18	1
SPTB	ENST00000389722.7	c.4779A>G	p.Ala1593=	synonymous_variant	22/35	2		P1
SPTB	ENST00000389720.4	c.4779A>G	p.Ala1593=	synonymous_variant	23/32	5

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8770 AN: 152228 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0439

GnomAD3 exomes AF: 0.0604 AC: 15180 AN: 251184 Hom.: 590 AF XY: 0.0608 AC XY: 8264 AN XY: 135836

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0408

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0262

Gnomad SAS exome AF: 0.0304

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0843

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0731 AC: 106788 AN: 1461558 Hom.: 4305 Cov.: 33 AF XY: 0.0722 AC XY: 52492 AN XY: 727106

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.0437

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.0304

Gnomad4 FIN exome AF: 0.0787

Gnomad4 NFE exome AF: 0.0821

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0576 AC: 8775 AN: 152346 Hom.: 296 Cov.: 32 AF XY: 0.0575 AC XY: 4286 AN XY: 74500

Gnomad4 AFR AF: 0.0191

Gnomad4 AMR AF: 0.0530

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0769

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0749 Hom.: 700

Bravo AF: 0.0534

Asia WGS AF: 0.0580 AC: 202 AN: 3478

EpiCase AF: 0.0759

EpiControl AF: 0.0762

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 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	-0.92
Cadd	Benign	0.0040
Dann	Benign	0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs4902310; hg19: chr14-65241906;