rs4902312

Variant names:

• chr14-64775407-C-T
• rs4902312
• NM_001355436.2:c.4564-4G>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.4564-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0714 in 1,609,878 control chromosomes in the GnomAD database, including 4,553 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (294 hom., cov: 33)
  • Exomes 𝑓: 0.073 (4259 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002860
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -4.71
• Publications: 7 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 (BayesDel_noAF=-0.78).
• BP6: Variant 14-64775407-C-T is Benign according to our data. Variant chr14-64775407-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.083 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.4564-4G>A		splice_region intron	N/A	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4564-4G>A		splice_region intron	N/A	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4564-4G>A		splice_region intron	N/A	NP_001342366.1	P11277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4564-4G>A		splice_region intron	N/A	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.559-4G>A		splice_region intron	N/A	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4564-4G>A		splice_region intron	N/A	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.0577 AC: 8775 AN: 152202 Hom.: 294 Cov.: 33

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0533

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0200

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0597 AC: 14713 AN: 246310 AF XY: 0.0602

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0407

Gnomad ASJ exome AF: 0.0506

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.0754

Gnomad NFE exome AF: 0.0836

Gnomad OTH exome AF: 0.0590

GnomAD4 exome AF: 0.0729 AC: 106225 AN: 1457558 Hom.: 4259 Cov.: 35 AF XY: 0.0720 AC XY: 52121 AN XY: 724344

African (AFR) AF: 0.0158 AC: 527 AN: 33410

American (AMR) AF: 0.0436 AC: 1944 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0517 AC: 1346 AN: 26028

East Asian (EAS) AF: 0.0166 AC: 657 AN: 39596

South Asian (SAS) AF: 0.0302 AC: 2600 AN: 86056

European-Finnish (FIN) AF: 0.0783 AC: 4152 AN: 52996

Middle Eastern (MID) AF: 0.0385 AC: 221 AN: 5734

European-Non Finnish (NFE) AF: 0.0819 AC: 90816 AN: 1108938

Other (OTH) AF: 0.0658 AC: 3962 AN: 60206

GnomAD4 genome AF: 0.0576 AC: 8777 AN: 152320 Hom.: 294 Cov.: 33 AF XY: 0.0576 AC XY: 4294 AN XY: 74494

African (AFR) AF: 0.0190 AC: 791 AN: 41580

American (AMR) AF: 0.0532 AC: 814 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3470

East Asian (EAS) AF: 0.0200 AC: 104 AN: 5194

South Asian (SAS) AF: 0.0292 AC: 141 AN: 4830

European-Finnish (FIN) AF: 0.0769 AC: 815 AN: 10604

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0848 AC: 5769 AN: 68020

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0722 Hom.: 350

Bravo AF: 0.0534

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0760

EpiControl AF: 0.0760

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Elliptocytosis (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.34
DANN	Benign	0.68
PhyloP100		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.020
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: rs4902312; hg19: chr14-65242125; COSMIC: COSV107501391;