rs229587

Variant names:

• chr14-64796582-C-T
• rs229587
• NM_001355436.2:c.1316G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001355436.2(SPTB):​c.1316G>A​(p.Ser439Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,916 control chromosomes in the GnomAD database, including 107,460 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15118 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92342 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.524
• Publications: 52 publications found

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]

SPTB Gene-Disease associations (from GenCC):

• hereditary spherocytosis type 2

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.087483E-6).
• BP6: Variant 14-64796582-C-T is Benign according to our data. Variant chr14-64796582-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001355436.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.1316G>A	p.Ser439Asn	missense	Exon 11 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.1316G>A	p.Ser439Asn	missense	Exon 10 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.1316G>A	p.Ser439Asn	missense	Exon 11 of 32	NP_001342366.1	P11277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.1316G>A	p.Ser439Asn	missense	Exon 11 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000389722.7	TSL:2	c.1316G>A	p.Ser439Asn	missense	Exon 10 of 35	ENSP00000374372.3	P11277-2
	SPTB	ENST00000961380.1		c.1316G>A	p.Ser439Asn	missense	Exon 12 of 37	ENSP00000631439.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64503 AN: 151966 Hom.: 15091 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.383

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.334

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.369 AC: 92811 AN: 251462 AF XY: 0.373

Gnomad AFR exome AF: 0.643

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.419

Gnomad EAS exome AF: 0.322

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.342

Gnomad OTH exome AF: 0.369

GnomAD4 exome AF: 0.348 AC: 509386 AN: 1461832 Hom.: 92342 Cov.: 62 AF XY: 0.353 AC XY: 256636 AN XY: 727222

African (AFR) AF: 0.645 AC: 21609 AN: 33478

American (AMR) AF: 0.282 AC: 12618 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.432 AC: 11280 AN: 26134

East Asian (EAS) AF: 0.336 AC: 13318 AN: 39696

South Asian (SAS) AF: 0.474 AC: 40909 AN: 86254

European-Finnish (FIN) AF: 0.324 AC: 17280 AN: 53408

Middle Eastern (MID) AF: 0.438 AC: 2526 AN: 5768

European-Non Finnish (NFE) AF: 0.330 AC: 367047 AN: 1111980

Other (OTH) AF: 0.378 AC: 22799 AN: 60392

GnomAD4 genome AF: 0.425 AC: 64573 AN: 152084 Hom.: 15118 Cov.: 32 AF XY: 0.423 AC XY: 31472 AN XY: 74322

African (AFR) AF: 0.634 AC: 26309 AN: 41496

American (AMR) AF: 0.336 AC: 5136 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1454 AN: 3472

East Asian (EAS) AF: 0.349 AC: 1798 AN: 5152

South Asian (SAS) AF: 0.485 AC: 2337 AN: 4816

European-Finnish (FIN) AF: 0.330 AC: 3490 AN: 10580

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.334 AC: 22680 AN: 67966

Other (OTH) AF: 0.418 AC: 884 AN: 2114

Alfa AF: 0.368 Hom.: 50829

Bravo AF: 0.432

TwinsUK AF: 0.332 AC: 1232

ALSPAC AF: 0.325 AC: 1254

ESP6500AA AF: 0.635 AC: 2796

ESP6500EA AF: 0.335 AC: 2879

ExAC AF: 0.380 AC: 46179

Asia WGS AF: 0.447 AC: 1554 AN: 3478

EpiCase AF: 0.352

EpiControl AF: 0.354

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Elliptocytosis (1)
-	-	1	Hereditary spherocytosis type 2 (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.8
DANN	Benign	0.76
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0000051	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.80	N
PhyloP100		0.52
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.046
Sift	Benign	0.44	T
Sift4G	Benign	0.49	T
Polyphen		0.0030	B
Vest4		0.017
MPC		0.18
ClinPred		0.016	T
GERP RS		0.77
Varity_R		0.11
gMVP		0.32
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs229587; hg19: chr14-65263300; COSMIC: COSV67631892;