14-64775326-C-T

Variant names:

• chr14-64775326-C-T
• rs184528
• NM_001355436.2:c.4641G>A

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.4641G>A​(p.Ala1547Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,612,852 control chromosomes in the GnomAD database, including 48,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (12396 hom., cov: 33)
  • Exomes 𝑓: 0.20 (36137 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.49
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 14-64775326-C-T is Benign according to our data. Variant chr14-64775326-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.49 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 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.4641G>A	p.Ala1547Ala	synonymous	Exon 23 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4641G>A	p.Ala1547Ala	synonymous	Exon 22 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4641G>A	p.Ala1547Ala	synonymous	Exon 23 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.4641G>A	p.Ala1547Ala	synonymous	Exon 23 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.636G>A	p.Ala212Ala	synonymous	Exon 4 of 18	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4641G>A	p.Ala1547Ala	synonymous	Exon 22 of 35	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51299 AN: 152056 Hom.: 12352 Cov.: 33

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.257 AC: 63957 AN: 248620 AF XY: 0.248

Gnomad AFR exome AF: 0.697

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.375

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.176

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.201 AC: 293218 AN: 1460678 Hom.: 36137 Cov.: 45 AF XY: 0.201 AC XY: 146165 AN XY: 726638

African (AFR) AF: 0.706 AC: 23623 AN: 33476

American (AMR) AF: 0.258 AC: 11530 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6228 AN: 26104

East Asian (EAS) AF: 0.408 AC: 16184 AN: 39670

South Asian (SAS) AF: 0.262 AC: 22575 AN: 86186

European-Finnish (FIN) AF: 0.243 AC: 12872 AN: 52966

Middle Eastern (MID) AF: 0.276 AC: 1591 AN: 5764

European-Non Finnish (NFE) AF: 0.166 AC: 184263 AN: 1111546

Other (OTH) AF: 0.238 AC: 14352 AN: 60360

GnomAD4 genome AF: 0.338 AC: 51399 AN: 152174 Hom.: 12396 Cov.: 33 AF XY: 0.337 AC XY: 25092 AN XY: 74392

African (AFR) AF: 0.681 AC: 28250 AN: 41510

American (AMR) AF: 0.258 AC: 3944 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1951 AN: 5174

South Asian (SAS) AF: 0.279 AC: 1350 AN: 4832

European-Finnish (FIN) AF: 0.251 AC: 2654 AN: 10580

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11486 AN: 67996

Other (OTH) AF: 0.320 AC: 675 AN: 2110

Alfa AF: 0.242 Hom.: 4611

Bravo AF: 0.359

Asia WGS AF: 0.318 AC: 1107 AN: 3478

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	Hereditary spherocytosis type 2 (1)
-	-	1	not specified (1)
-	-	1	Spherocytosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.59
DANN	Benign	0.56
PhyloP100		-5.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=92/8	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: rs184528; hg19: chr14-65242044; COSMIC: COSV67630111;