NM_001355436.2:c.4476T>C

Variant names:

• chr14-64779244-A-G
• rs1741487
• NM_001355436.2:c.4476T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.4476T>C​(p.Leu1492Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,602,920 control chromosomes in the GnomAD database, including 61,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (11193 hom., cov: 32)
  • Exomes 𝑓: 0.25 (50692 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0400
• Publications: 14 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: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 14-64779244-A-G is Benign according to our data. Variant chr14-64779244-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.607 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4476T>C	p.Leu1492Leu	splice_region synonymous	Exon 22 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.4476T>C	p.Leu1492Leu	splice_region synonymous	Exon 21 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.4476T>C	p.Leu1492Leu	splice_region synonymous	Exon 22 of 32	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4476T>C	p.Leu1492Leu	splice_region synonymous	Exon 22 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.471T>C	p.Leu157Leu	splice_region synonymous	Exon 3 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4476T>C	p.Leu1492Leu	splice_region synonymous	Exon 21 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51806 AN: 151738 Hom.: 11166 Cov.: 32

Gnomad AFR AF: 0.613

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.325

GnomAD2 exomes AF: 0.267 AC: 66169 AN: 248078 AF XY: 0.269

Gnomad AFR exome AF: 0.618

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.260

Gnomad EAS exome AF: 0.329

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.228

Gnomad OTH exome AF: 0.262

GnomAD4 exome AF: 0.251 AC: 363768 AN: 1451064 Hom.: 50692 Cov.: 32 AF XY: 0.254 AC XY: 183048 AN XY: 722028

African (AFR) AF: 0.633 AC: 21006 AN: 33174

American (AMR) AF: 0.145 AC: 6460 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6944 AN: 26012

East Asian (EAS) AF: 0.321 AC: 12683 AN: 39474

South Asian (SAS) AF: 0.366 AC: 31331 AN: 85646

European-Finnish (FIN) AF: 0.220 AC: 11700 AN: 53202

Middle Eastern (MID) AF: 0.298 AC: 1710 AN: 5732

European-Non Finnish (NFE) AF: 0.231 AC: 254995 AN: 1103180

Other (OTH) AF: 0.282 AC: 16939 AN: 60038

GnomAD4 genome AF: 0.342 AC: 51871 AN: 151856 Hom.: 11193 Cov.: 32 AF XY: 0.340 AC XY: 25207 AN XY: 74226

African (AFR) AF: 0.613 AC: 25330 AN: 41318

American (AMR) AF: 0.209 AC: 3187 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3470

East Asian (EAS) AF: 0.337 AC: 1735 AN: 5154

South Asian (SAS) AF: 0.381 AC: 1836 AN: 4816

European-Finnish (FIN) AF: 0.228 AC: 2410 AN: 10580

Middle Eastern (MID) AF: 0.323 AC: 95 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15472 AN: 67930

Other (OTH) AF: 0.321 AC: 676 AN: 2106

Alfa AF: 0.273 Hom.: 14492

Bravo AF: 0.350

Asia WGS AF: 0.370 AC: 1289 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Elliptocytosis Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spherocytosis, Dominant Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary spherocytosis type 2 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.8
DANN	Benign	0.75
PhyloP100		0.040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs1741487; hg19: chr14-65245962; COSMIC: COSV67631364;