14-64775349-T-G

Variant names:

• chr14-64775349-T-G
• rs61989884
• NM_001355436.2:c.4618A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001355436.2(SPTB):​c.4618A>C​(p.Arg1540Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,613,402 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0032 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (30 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.04
• Publications: 1 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=-0.64).
• BP6: Variant 14-64775349-T-G is Benign according to our data. Variant chr14-64775349-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00316 (482/152324) while in subpopulation NFE AF = 0.00575 (391/68030). AF 95% confidence interval is 0.00528. There are 3 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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.4618A>C	p.Arg1540Arg	synonymous	Exon 23 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.4618A>C	p.Arg1540Arg	synonymous	Exon 22 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.4618A>C	p.Arg1540Arg	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.4618A>C	p.Arg1540Arg	synonymous	Exon 23 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.613A>C	p.Arg205Arg	synonymous	Exon 4 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4618A>C	p.Arg1540Arg	synonymous	Exon 22 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152206 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00575

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00308 AC: 768 AN: 249650 AF XY: 0.00323

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000956

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00531

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00494 AC: 7212 AN: 1461078 Hom.: 30 Cov.: 35 AF XY: 0.00484 AC XY: 3516 AN XY: 726788

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.000940 AC: 42 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00107 AC: 28 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86210

European-Finnish (FIN) AF: 0.00218 AC: 116 AN: 53100

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00591 AC: 6575 AN: 1111658

Other (OTH) AF: 0.00381 AC: 230 AN: 60380

GnomAD4 genome AF: 0.00316 AC: 482 AN: 152324 Hom.: 3 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74484

African (AFR) AF: 0.00111 AC: 46 AN: 41570

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68030

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00506 Hom.: 0

Bravo AF: 0.00302

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SPTB: BP4, BP7, BS2

May 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

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	-0.64
CADD	Benign	10
DANN	Benign	0.62
PhyloP100		1.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2
Mutation Taster		=94/6	polymorphism

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: rs61989884; hg19: chr14-65242067;