rs3742601

chr14-64793825-C-A

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.1838G>T(p.Ser613Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,611,054 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (17 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0270

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=0.0066212714).
• BP6: Variant 14-64793825-C-A is Benign according to our data. Variant chr14-64793825-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 257100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64793825-C-A is described in Lovd as [Benign]. Variant chr14-64793825-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00139 (212/152136) while in subpopulation EAS AF= 0.0171 (88/5154). AF 95% confidence interval is 0.0142. There are 2 homozygotes in gnomad4. There are 109 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.1838G>T	p.Ser613Ile	missense_variant	14/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.1838G>T	p.Ser613Ile	missense_variant	14/36		NM_001355436.2	P1
SPTB	ENST00000389722.7	c.1838G>T	p.Ser613Ile	missense_variant	13/35	2		P1
SPTB	ENST00000389720.4	c.1838G>T	p.Ser613Ile	missense_variant	14/32	5

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 203 AN: 152008 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00518

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0170

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00284 AC: 701 AN: 247250 Hom.: 4 AF XY: 0.00233 AC XY: 313 AN XY: 134144

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00908

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0188

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.000986 AC: 1439 AN: 1458918 Hom.: 17 Cov.: 36 AF XY: 0.000956 AC XY: 694 AN XY: 725974

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00957

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00354

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152136 Hom.: 2 Cov.: 32 AF XY: 0.00147 AC XY: 109 AN XY: 74392

Gnomad4 AFR AF: 0.000506

Gnomad4 AMR AF: 0.00524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0171

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00127 Hom.: 8

Bravo AF: 0.00196

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	Dec 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.078
Eigen_PC	Benign	-0.026
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D;.;D;D;D
REVEL	Benign	0.11
Sift	Benign	0.099	T;.;T;T;T
Sift4G	Benign	0.14	T;.;T;T;T
Polyphen		0.29	.;.;.;B;B
Vest4		0.44
MVP		0.34
MPC		0.57
ClinPred		0.032	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.32

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: rs3742601; hg19: chr14-65260543;