rs78707026

Variant names:

• chr14-64782565-A-G
• rs78707026
• NM_001355436.2:c.4003-12T>C

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.4003-12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 1,613,164 control chromosomes in the GnomAD database, including 5,118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (334 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4784 hom.)
• Consequence: SPTB NM_001355436.2 intron
• Scores: Splicing: ADA: 0.0001462
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.542
• Publications: 3 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=-0.8).
• BP6: Variant 14-64782565-A-G is Benign according to our data. Variant chr14-64782565-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0884 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.4003-12T>C		intron	N/A	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4003-12T>C		intron	N/A	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4003-12T>C		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.4003-12T>C		intron	N/A	ENSP00000495909.1	P11277-2
	SPTB	ENST00000389722.7	TSL:2	c.4003-12T>C		intron	N/A	ENSP00000374372.3	P11277-2
	SPTB	ENST00000961380.1		c.4003-12T>C		intron	N/A	ENSP00000631439.1

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9106 AN: 152170 Hom.: 330 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0563

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.0256

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0752

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.0474

GnomAD2 exomes AF: 0.0635 AC: 15582 AN: 245258 AF XY: 0.0641

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0442

Gnomad ASJ exome AF: 0.0642

Gnomad EAS exome AF: 0.0298

Gnomad FIN exome AF: 0.0733

Gnomad NFE exome AF: 0.0894

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0774 AC: 113010 AN: 1460876 Hom.: 4784 Cov.: 33 AF XY: 0.0766 AC XY: 55701 AN XY: 726750

African (AFR) AF: 0.0119 AC: 398 AN: 33474

American (AMR) AF: 0.0468 AC: 2094 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0642 AC: 1677 AN: 26134

East Asian (EAS) AF: 0.0300 AC: 1190 AN: 39700

South Asian (SAS) AF: 0.0320 AC: 2760 AN: 86254

European-Finnish (FIN) AF: 0.0759 AC: 3985 AN: 52512

Middle Eastern (MID) AF: 0.0428 AC: 246 AN: 5754

European-Non Finnish (NFE) AF: 0.0867 AC: 96441 AN: 1111956

Other (OTH) AF: 0.0699 AC: 4219 AN: 60376

GnomAD4 genome AF: 0.0599 AC: 9116 AN: 152288 Hom.: 334 Cov.: 32 AF XY: 0.0593 AC XY: 4418 AN XY: 74482

African (AFR) AF: 0.0152 AC: 631 AN: 41572

American (AMR) AF: 0.0562 AC: 860 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0669 AC: 232 AN: 3470

East Asian (EAS) AF: 0.0256 AC: 133 AN: 5188

South Asian (SAS) AF: 0.0311 AC: 150 AN: 4828

European-Finnish (FIN) AF: 0.0752 AC: 798 AN: 10616

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0903 AC: 6139 AN: 67996

Other (OTH) AF: 0.0530 AC: 112 AN: 2112

Alfa AF: 0.0755 Hom.: 116

Bravo AF: 0.0557

Asia WGS AF: 0.0580 AC: 200 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.2
DANN	Benign	0.77
PhyloP100		-0.54
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.060		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: rs78707026; hg19: chr14-65249283;