rs4899145

Positions:

• chr14-64775149-G-A
• chr14-64775149-G-T

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.4818C>T​(p.Tyr1606Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,884 control chromosomes in the GnomAD database, including 4,602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (296 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4306 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0440

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=-0.53).
• BP6: Variant 14-64775149-G-A is Benign according to our data. Variant chr14-64775149-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64775149-G-A is described in Lovd as [Benign]. Variant chr14-64775149-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.044 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	Protein	UniProt
SPTB	NM_001355436.2	c.4818C>T	p.Tyr1606Tyr	synonymous_variant	23/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.4818C>T	p.Tyr1606Tyr	synonymous_variant	23/36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.813C>T	p.Tyr271Tyr	synonymous_variant	4/18	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.4818C>T	p.Tyr1606Tyr	synonymous_variant	22/35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.4818C>T	p.Tyr1606Tyr	synonymous_variant	23/32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8910 AN: 152180 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0607 AC: 15211 AN: 250798 Hom.: 590 AF XY: 0.0610 AC XY: 8270 AN XY: 135654

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0261

Gnomad SAS exome AF: 0.0303

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0842

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0731 AC: 106893 AN: 1461586 Hom.: 4306 Cov.: 33 AF XY: 0.0722 AC XY: 52530 AN XY: 727114

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.0518

Gnomad4 EAS exome AF: 0.0165

Gnomad4 SAS exome AF: 0.0303

Gnomad4 FIN exome AF: 0.0786

Gnomad4 NFE exome AF: 0.0821

Gnomad4 OTH exome AF: 0.0663

GnomAD4 genome AF: 0.0585 AC: 8912 AN: 152298 Hom.: 296 Cov.: 32 AF XY: 0.0585 AC XY: 4354 AN XY: 74460

Gnomad4 AFR AF: 0.0224

Gnomad4 AMR AF: 0.0536

Gnomad4 ASJ AF: 0.0550

Gnomad4 EAS AF: 0.0197

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0767

Gnomad4 NFE AF: 0.0847

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0732 Hom.: 344

Bravo AF: 0.0544

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0759

EpiControl AF: 0.0763

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	- -
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 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	-0.53
CADD	Benign	1.8
DANN	Benign	0.25
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: rs4899145; hg19: chr14-65241867;