14-64779238-C-T

Position:

• chr14-64779238-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.4482G>A​(p.Val1494Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,604,858 control chromosomes in the GnomAD database, including 61,948 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11186 hom., cov: 32)
  • Exomes 𝑓: 0.25 (50762 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.432

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=-0.29).
• BP6: Variant 14-64779238-C-T is Benign according to our data. Variant chr14-64779238-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64779238-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.432 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	Protein	UniProt
SPTB	NM_001355436.2	c.4482G>A	p.Val1494Val	synonymous_variant	22/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.4482G>A	p.Val1494Val	synonymous_variant	22/36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.477G>A	p.Val159Val	synonymous_variant	3/18	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.4482G>A	p.Val1494Val	synonymous_variant	21/35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.4482G>A	p.Val1494Val	synonymous_variant	22/32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51788 AN: 151730 Hom.: 11159 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.381

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: 66453 AN: 248638 Hom.: 10526 AF XY: 0.269 AC XY: 36207 AN XY: 134438

Gnomad AFR exome AF: 0.619

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: 364781 AN: 1453010 Hom.: 50762 Cov.: 32 AF XY: 0.254 AC XY: 183546 AN XY: 722990

Gnomad4 AFR exome AF: 0.633

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.220

Gnomad4 NFE exome AF: 0.232

Gnomad4 OTH exome AF: 0.282

GnomAD4 genome AF: 0.341 AC: 51853 AN: 151848 Hom.: 11186 Cov.: 32 AF XY: 0.339 AC XY: 25198 AN XY: 74232

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.262

Gnomad4 EAS AF: 0.337

Gnomad4 SAS AF: 0.380

Gnomad4 FIN AF: 0.228

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.321

Alfa AF: 0.256 Hom.: 10854

Bravo AF: 0.350

Asia WGS AF: 0.370 AC: 1287 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	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

- -

Hereditary spherocytosis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

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	-0.29
CADD	Benign	11
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)		0.010		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: rs1741488; hg19: chr14-65245956; COSMIC: COSV67631360;