rs3742602

chr14-64793603-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001355436.2(SPTB):c.2060G>A(p.Arg687His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,614,186 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R687C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (8 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.456

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=0.0073363483).
• BP6: Variant 14-64793603-C-T is Benign according to our data. Variant chr14-64793603-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 257101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64793603-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (196/152330) while in subpopulation EAS AF= 0.0147 (76/5184). AF 95% confidence interval is 0.012. There are 1 homozygotes in gnomad4. There are 106 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.2060G>A	p.Arg687His	missense_variant	14/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.2060G>A	p.Arg687His	missense_variant	14/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.2060G>A	p.Arg687His	missense_variant	13/35	2		P1
SPTB	ENST00000389720.4	c.2060G>A	p.Arg687His	missense_variant	14/32	5

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 195 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00510

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00258 AC: 648 AN: 250826 Hom.: 4 AF XY: 0.00209 AC XY: 284 AN XY: 135608

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00911

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000901 AC: 1317 AN: 1461856 Hom.: 8 Cov.: 36 AF XY: 0.000862 AC XY: 627 AN XY: 727222

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00948

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0160

Gnomad4 SAS exome AF: 0.000487

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000872

Gnomad4 OTH exome AF: 0.00185

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74482

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0147

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000899 Hom.: 1

Bravo AF: 0.00179

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00240 AC: 291

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -

not specified Benign:1

Likely 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	0.076
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Pathogenic	1.0
Eigen	Benign	0.13
Eigen_PC	Benign	0.027
FATHMM_MKL	Benign	0.43	N
MetaRNN	Benign	0.0073	T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.7	L;L;L;L;L
MutationTaster	Benign	0.96	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.039	D;.;D;D;D
Sift4G	Benign	0.091	T;.;T;T;T
Polyphen		1.0	.;.;.;D;D
Vest4		0.12
MVP		0.49
MPC		0.76
ClinPred		0.014	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.12
gMVP		0.22

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: rs3742602; hg19: chr14-65260321; COSMIC: COSV67630455;