14-64775188-T-C

Variant names:

• chr14-64775188-T-C
• rs4902310
• NM_001355436.2:c.4779A>G

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.4779A>G​(p.Ala1593Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0716 in 1,613,904 control chromosomes in the GnomAD database, including 4,601 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (296 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4305 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -8.17
• Publications: 13 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=-0.92).
• BP6: Variant 14-64775188-T-C is Benign according to our data. Variant chr14-64775188-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.17 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4779A>G	p.Ala1593Ala	synonymous	Exon 23 of 36	NP_001342365.1
	SPTB	NM_001024858.4		c.4779A>G	p.Ala1593Ala	synonymous	Exon 22 of 35	NP_001020029.1
	SPTB	NM_001355437.2		c.4779A>G	p.Ala1593Ala	synonymous	Exon 23 of 32	NP_001342366.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	ENST00000644917.1	MANE Select	c.4779A>G	p.Ala1593Ala	synonymous	Exon 23 of 36	ENSP00000495909.1
	SPTB	ENST00000553938.5	TSL:1	c.774A>G	p.Ala258Ala	synonymous	Exon 4 of 18	ENSP00000451324.1
	SPTB	ENST00000389722.7	TSL:2	c.4779A>G	p.Ala1593Ala	synonymous	Exon 22 of 35	ENSP00000374372.3

Frequencies

GnomAD3 genomes AF: 0.0576 AC: 8770 AN: 152228 Hom.: 296 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0531

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0289

Gnomad FIN AF: 0.0769

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0848

Gnomad OTH AF: 0.0439

GnomAD2 exomes AF: 0.0604 AC: 15180 AN: 251184 AF XY: 0.0608

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0408

Gnomad ASJ exome AF: 0.0505

Gnomad EAS exome AF: 0.0262

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0843

Gnomad OTH exome AF: 0.0602

GnomAD4 exome AF: 0.0731 AC: 106788 AN: 1461558 Hom.: 4305 Cov.: 33 AF XY: 0.0722 AC XY: 52492 AN XY: 727106

African (AFR) AF: 0.0160 AC: 536 AN: 33480

American (AMR) AF: 0.0437 AC: 1954 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 1355 AN: 26134

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

South Asian (SAS) AF: 0.0304 AC: 2618 AN: 86258

European-Finnish (FIN) AF: 0.0787 AC: 4181 AN: 53140

Middle Eastern (MID) AF: 0.0385 AC: 222 AN: 5768

European-Non Finnish (NFE) AF: 0.0821 AC: 91274 AN: 1111966

Other (OTH) AF: 0.0661 AC: 3991 AN: 60388

GnomAD4 genome AF: 0.0576 AC: 8775 AN: 152346 Hom.: 296 Cov.: 32 AF XY: 0.0575 AC XY: 4286 AN XY: 74500

African (AFR) AF: 0.0191 AC: 795 AN: 41584

American (AMR) AF: 0.0530 AC: 812 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3468

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5188

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4832

European-Finnish (FIN) AF: 0.0769 AC: 817 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0848 AC: 5766 AN: 68018

Other (OTH) AF: 0.0449 AC: 95 AN: 2116

Alfa AF: 0.0735 Hom.: 997

Bravo AF: 0.0534

Asia WGS AF: 0.0580 AC: 202 AN: 3478

EpiCase AF: 0.0759

EpiControl AF: 0.0762

ClinVar

ClinVar submissions as Germline

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	-0.92
CADD	Benign	0.0040
DANN	Benign	0.30
PhyloP100		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=67/33	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: rs4902310; hg19: chr14-65241906; COSMIC: COSV107501390;