chr14-64796629-C-T

Position:

• chr14-64796629-C-T

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.1269G>A​(p.Leu423=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 1,614,024 control chromosomes in the GnomAD database, including 53,837 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5071 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48766 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.265

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=-0.39).
• BP6: Variant 14-64796629-C-T is Benign according to our data. Variant chr14-64796629-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64796629-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.265 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.1269G>A	p.Leu423=	synonymous_variant	11/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.1269G>A	p.Leu423=	synonymous_variant	11/36		NM_001355436.2	ENSP00000495909	P1
SPTB	ENST00000389722.7	c.1269G>A	p.Leu423=	synonymous_variant	10/35	2		ENSP00000374372	P1
SPTB	ENST00000389720.4	c.1269G>A	p.Leu423=	synonymous_variant	11/32	5		ENSP00000374370

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38868 AN: 152066 Hom.: 5067 Cov.: 32

Gnomad AFR AF: 0.268

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.250

Gnomad OTH AF: 0.261

GnomAD3 exomes AF: 0.259 AC: 65031 AN: 251418 Hom.: 8798 AF XY: 0.266 AC XY: 36124 AN XY: 135886

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.185

Gnomad ASJ exome AF: 0.255

Gnomad EAS exome AF: 0.263

Gnomad SAS exome AF: 0.375

Gnomad FIN exome AF: 0.222

Gnomad NFE exome AF: 0.255

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.254 AC: 371754 AN: 1461838 Hom.: 48766 Cov.: 42 AF XY: 0.259 AC XY: 188322 AN XY: 727228

Gnomad4 AFR exome AF: 0.270

Gnomad4 AMR exome AF: 0.193

Gnomad4 ASJ exome AF: 0.265

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.256 AC: 38888 AN: 152186 Hom.: 5071 Cov.: 32 AF XY: 0.256 AC XY: 19065 AN XY: 74410

Gnomad4 AFR AF: 0.268

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.249

Gnomad4 OTH AF: 0.257

Alfa AF: 0.248 Hom.: 7924

Bravo AF: 0.253

Asia WGS AF: 0.342 AC: 1187 AN: 3478

EpiCase AF: 0.256

EpiControl AF: 0.256

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	- -
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 28, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

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	-0.39
CADD	Benign	9.0
DANN	Benign	0.76
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: rs229586; hg19: chr14-65263347; COSMIC: COSV67630508;