14-64782348-C-T

Variant names:

• chr14-64782348-C-T
• rs17180350
• NM_001355436.2:c.4208G>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.4208G>A​(p.Arg1403Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 1,614,140 control chromosomes in the GnomAD database, including 5,126 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1403P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.060 (336 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4790 hom.)
• Consequence: SPTB NM_001355436.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.29
• Publications: 24 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=0.002068013).
• BP6: Variant 14-64782348-C-T is Benign according to our data. Variant chr14-64782348-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257114.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.4208G>A	p.Arg1403Gln	missense	Exon 20 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4208G>A	p.Arg1403Gln	missense	Exon 19 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4208G>A	p.Arg1403Gln	missense	Exon 20 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.4208G>A	p.Arg1403Gln	missense	Exon 20 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.203G>A	p.Arg68Gln	missense	Exon 1 of 18	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4208G>A	p.Arg1403Gln	missense	Exon 19 of 35	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.0599 AC: 9113 AN: 152158 Hom.: 332 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0669

Gnomad EAS AF: 0.0258

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0753

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0903

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0640 AC: 16087 AN: 251430 AF XY: 0.0646

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.0441

Gnomad ASJ exome AF: 0.0638

Gnomad EAS exome AF: 0.0301

Gnomad FIN exome AF: 0.0739

Gnomad NFE exome AF: 0.0895

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0774 AC: 113122 AN: 1461866 Hom.: 4790 Cov.: 32 AF XY: 0.0767 AC XY: 55764 AN XY: 727242

African (AFR) AF: 0.0119 AC: 400 AN: 33480

American (AMR) AF: 0.0468 AC: 2091 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0643 AC: 1681 AN: 26136

East Asian (EAS) AF: 0.0300 AC: 1191 AN: 39700

South Asian (SAS) AF: 0.0322 AC: 2778 AN: 86258

European-Finnish (FIN) AF: 0.0763 AC: 4072 AN: 53392

Middle Eastern (MID) AF: 0.0425 AC: 245 AN: 5768

European-Non Finnish (NFE) AF: 0.0867 AC: 96446 AN: 1112012

Other (OTH) AF: 0.0698 AC: 4218 AN: 60396

GnomAD4 genome AF: 0.0599 AC: 9123 AN: 152274 Hom.: 336 Cov.: 32 AF XY: 0.0594 AC XY: 4423 AN XY: 74464

African (AFR) AF: 0.0153 AC: 634 AN: 41560

American (AMR) AF: 0.0561 AC: 859 AN: 15306

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

East Asian (EAS) AF: 0.0258 AC: 134 AN: 5186

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4828

European-Finnish (FIN) AF: 0.0753 AC: 799 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0903 AC: 6142 AN: 68004

Other (OTH) AF: 0.0526 AC: 111 AN: 2110

Alfa AF: 0.0764 Hom.: 1432

Bravo AF: 0.0558

TwinsUK AF: 0.0882 AC: 327

ALSPAC AF: 0.0903 AC: 348

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.0810 AC: 697

ExAC AF: 0.0641 AC: 7781

Asia WGS AF: 0.0570 AC: 197 AN: 3478

EpiCase AF: 0.0835

EpiControl AF: 0.0830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Benign	0.41
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.35	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.39	N
PhyloP100		1.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.075
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.033
MPC		0.22
ClinPred		0.0039	T
GERP RS		4.5
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.053
gMVP		0.066
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: rs17180350; hg19: chr14-65249066; COSMIC: COSV107501306; COSMIC: COSV107501306;