rs10132778

Positions:

• chr14-64782435-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.4121A>G​(p.His1374Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0328 in 1,614,044 control chromosomes in the GnomAD database, including 1,041 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (97 hom., cov: 32)
  • Exomes 𝑓: 0.033 (944 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.503

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020920336).
• BP6: Variant 14-64782435-T-C is Benign according to our data. Variant chr14-64782435-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64782435-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4121A>G	p.His1374Arg	missense_variant	20/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4121A>G	p.His1374Arg	missense_variant	20/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.116A>G	p.His39Arg	missense_variant	1/18	1
SPTB	ENST00000389722.7	c.4121A>G	p.His1374Arg	missense_variant	19/35	2		P1
SPTB	ENST00000389720.4	c.4121A>G	p.His1374Arg	missense_variant	20/32	5

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5272 AN: 152092 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0447

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0307

GnomAD3 exomes AF: 0.0328 AC: 8254 AN: 251390 Hom.: 189 AF XY: 0.0348 AC XY: 4724 AN XY: 135876

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.0208

Gnomad ASJ exome AF: 0.0507

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0651

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0307

Gnomad OTH exome AF: 0.0437

GnomAD4 exome AF: 0.0326 AC: 47651 AN: 1461834 Hom.: 944 Cov.: 33 AF XY: 0.0339 AC XY: 24677 AN XY: 727220

Gnomad4 AFR exome AF: 0.0463

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0522

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0680

Gnomad4 FIN exome AF: 0.0270

Gnomad4 NFE exome AF: 0.0308

Gnomad4 OTH exome AF: 0.0335

GnomAD4 genome AF: 0.0346 AC: 5271 AN: 152210 Hom.: 97 Cov.: 32 AF XY: 0.0344 AC XY: 2559 AN XY: 74416

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.0214

Gnomad4 ASJ AF: 0.0507

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0664

Gnomad4 FIN AF: 0.0260

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0303

Alfa AF: 0.0311 Hom.: 159

Bravo AF: 0.0338

TwinsUK AF: 0.0305 AC: 113

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.0316 AC: 272

ExAC AF: 0.0340 AC: 4123

Asia WGS AF: 0.0290 AC: 100 AN: 3478

EpiCase AF: 0.0320

EpiControl AF: 0.0302

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	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.46
DANN	Benign	0.17
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.051	N
MetaRNN	Benign	0.0021	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.54	N;N;N;.;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.59	N;.;N;N;N;N
REVEL	Benign	0.018
Sift	Benign	1.0	T;.;T;T;T;T
Sift4G	Benign	0.83	T;.;T;T;T;T
Polyphen		0.0	.;.;.;.;B;B
Vest4		0.0060
MPC		0.23
ClinPred		0.0011	T
GERP RS		-3.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.029
gMVP		0.12

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: rs10132778; hg19: chr14-65249153;