rs1741487

Positions:

• chr14-64779244-A-G

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.4476T>C​(p.Leu1492=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,602,920 control chromosomes in the GnomAD database, including 61,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11193 hom., cov: 32)
  • Exomes 𝑓: 0.25 (50692 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0400

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=-0.42).
• BP6: Variant 14-64779244-A-G is Benign according to our data. Variant chr14-64779244-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64779244-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4476T>C	p.Leu1492=	splice_region_variant, synonymous_variant	22/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4476T>C	p.Leu1492=	splice_region_variant, synonymous_variant	22/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.471T>C	p.Leu157=	splice_region_variant, synonymous_variant	3/18	1
SPTB	ENST00000389722.7	c.4476T>C	p.Leu1492=	splice_region_variant, synonymous_variant	21/35	2		P1
SPTB	ENST00000389720.4	c.4476T>C	p.Leu1492=	splice_region_variant, synonymous_variant	22/32	5

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51806 AN: 151738 Hom.: 11166 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.325

GnomAD3 exomes AF: 0.267 AC: 66169 AN: 248078 Hom.: 10463 AF XY: 0.269 AC XY: 36060 AN XY: 134136

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.329

Gnomad SAS exome AF: 0.373

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.251 AC: 363768 AN: 1451064 Hom.: 50692 Cov.: 32 AF XY: 0.254 AC XY: 183048 AN XY: 722028

Gnomad4 AFR exome AF: 0.633

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.321

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.231

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.342 AC: 51871 AN: 151856 Hom.: 11193 Cov.: 32 AF XY: 0.340 AC XY: 25207 AN XY: 74226

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.381

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.321

Alfa AF: 0.254 Hom.: 8432

Bravo AF: 0.350

Asia WGS AF: 0.370 AC: 1289 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

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 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 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

- -

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	-0.42
CADD	Benign	9.8
DANN	Benign	0.75
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: rs1741487; hg19: chr14-65245962; COSMIC: COSV67631364;