chr14-64775149-G-A

Variant names:

• chr14-64775149-G-A
• rs4899145
• NM_001355436.2:c.4818C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001355436.2(SPTB):​c.4818C>T​(p.Tyr1606Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0718 in 1,613,884 control chromosomes in the GnomAD database, including 4,602 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (296 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4306 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0440
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-64775149-G-A is Benign according to our data. Variant chr14-64775149-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.044 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0829 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.4818C>T	p.Tyr1606Tyr	synonymous	Exon 23 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.4818C>T	p.Tyr1606Tyr	synonymous	Exon 22 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.4818C>T	p.Tyr1606Tyr	synonymous	Exon 23 of 32	NP_001342366.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4818C>T	p.Tyr1606Tyr	synonymous	Exon 23 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.813C>T	p.Tyr271Tyr	synonymous	Exon 4 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4818C>T	p.Tyr1606Tyr	synonymous	Exon 22 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8910 AN: 152180 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0550

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.0286

Gnomad FIN AF: 0.0767

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.0440

GnomAD2 exomes AF: 0.0607 AC: 15211 AN: 250798 AF XY: 0.0610

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.0411

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0261

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0842

Gnomad OTH exome AF: 0.0603

GnomAD4 exome AF: 0.0731 AC: 106893 AN: 1461586 Hom.: 4306 Cov.: 33 AF XY: 0.0722 AC XY: 52530 AN XY: 727114

African (AFR) AF: 0.0184 AC: 615 AN: 33480

American (AMR) AF: 0.0440 AC: 1966 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 1355 AN: 26136

East Asian (EAS) AF: 0.0165 AC: 657 AN: 39700

South Asian (SAS) AF: 0.0303 AC: 2611 AN: 86258

European-Finnish (FIN) AF: 0.0786 AC: 4179 AN: 53150

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0821 AC: 91282 AN: 1111980

Other (OTH) AF: 0.0663 AC: 4002 AN: 60390

GnomAD4 genome AF: 0.0585 AC: 8912 AN: 152298 Hom.: 296 Cov.: 32 AF XY: 0.0585 AC XY: 4354 AN XY: 74460

African (AFR) AF: 0.0224 AC: 932 AN: 41568

American (AMR) AF: 0.0536 AC: 820 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0550 AC: 191 AN: 3470

East Asian (EAS) AF: 0.0197 AC: 102 AN: 5186

South Asian (SAS) AF: 0.0284 AC: 137 AN: 4822

European-Finnish (FIN) AF: 0.0767 AC: 814 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0847 AC: 5763 AN: 68020

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

Alfa AF: 0.0740 Hom.: 999

Bravo AF: 0.0544

Asia WGS AF: 0.0580 AC: 201 AN: 3478

EpiCase AF: 0.0759

EpiControl AF: 0.0763

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.8
DANN	Benign	0.25
PhyloP100		-0.044
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	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: rs4899145; hg19: chr14-65241867; COSMIC: COSV107501389;