rs4902311

Positions:

• chr14-64775215-G-A
• chr14-64775215-G-C

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.4752C>T​(p.Asn1584=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0715 in 1,613,800 control chromosomes in the GnomAD database, including 4,598 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (296 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4302 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.672

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=-0.36).
• BP6: Variant 14-64775215-G-A is Benign according to our data. Variant chr14-64775215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64775215-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.672 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4752C>T	p.Asn1584=	synonymous_variant	23/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4752C>T	p.Asn1584=	synonymous_variant	23/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.747C>T	p.Asn249=	synonymous_variant	4/18	1
SPTB	ENST00000389722.7	c.4752C>T	p.Asn1584=	synonymous_variant	22/35	2		P1
SPTB	ENST00000389720.4	c.4752C>T	p.Asn1584=	synonymous_variant	23/32	5

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8725 AN: 152184 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0530

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.0772

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0435

GnomAD3 exomes AF: 0.0603 AC: 15135 AN: 251122 Hom.: 586 AF XY: 0.0607 AC XY: 8249 AN XY: 135834

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0253

Gnomad SAS exome AF: 0.0304

Gnomad FIN exome AF: 0.0763

Gnomad NFE exome AF: 0.0842

Gnomad OTH exome AF: 0.0604

GnomAD4 exome AF: 0.0730 AC: 106737 AN: 1461498 Hom.: 4302 Cov.: 33 AF XY: 0.0722 AC XY: 52475 AN XY: 727074

Gnomad4 AFR exome AF: 0.0147

Gnomad4 AMR exome AF: 0.0436

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.0161

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.0788

Gnomad4 NFE exome AF: 0.0821

Gnomad4 OTH exome AF: 0.0660

GnomAD4 genome AF: 0.0573 AC: 8730 AN: 152302 Hom.: 296 Cov.: 32 AF XY: 0.0572 AC XY: 4263 AN XY: 74464

Gnomad4 AFR AF: 0.0182

Gnomad4 AMR AF: 0.0529

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0772

Gnomad4 NFE AF: 0.0848

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0728 Hom.: 785

Bravo AF: 0.0531

Asia WGS AF: 0.0570 AC: 200 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	-0.36
CADD	Benign	5.7
DANN	Benign	0.83
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: rs4902311; hg19: chr14-65241933; COSMIC: COSV67636304;