14-64779238-C-T

Variant names:

• chr14-64779238-C-T
• rs1741488
• NM_001355436.2:c.4482G>A

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.4482G>A​(p.Val1494Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.26 in 1,604,858 control chromosomes in the GnomAD database, including 61,948 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 (11186 hom., cov: 32)
  • Exomes 𝑓: 0.25 (50762 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.432
• Publications: 18 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 14-64779238-C-T is Benign according to our data. Variant chr14-64779238-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.432 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTB	NM_001355436.2	MANE Select	c.4482G>A	p.Val1494Val	synonymous	Exon 22 of 36	NP_001342365.1	P11277-2
	SPTB	NM_001024858.4		c.4482G>A	p.Val1494Val	synonymous	Exon 21 of 35	NP_001020029.1	P11277-2
	SPTB	NM_001355437.2		c.4482G>A	p.Val1494Val	synonymous	Exon 22 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.4482G>A	p.Val1494Val	synonymous	Exon 22 of 36	ENSP00000495909.1	P11277-2
	SPTB	ENST00000553938.5	TSL:1	c.477G>A	p.Val159Val	synonymous	Exon 3 of 18	ENSP00000451324.1	H0YJE6
	SPTB	ENST00000389722.7	TSL:2	c.4482G>A	p.Val1494Val	synonymous	Exon 21 of 35	ENSP00000374372.3	P11277-2

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51788 AN: 151730 Hom.: 11159 Cov.: 32

Gnomad AFR AF: 0.612

Gnomad AMI AF: 0.244

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.381

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: 66453 AN: 248638 AF XY: 0.269

Gnomad AFR exome AF: 0.619

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: 364781 AN: 1453010 Hom.: 50762 Cov.: 32 AF XY: 0.254 AC XY: 183546 AN XY: 722990

African (AFR) AF: 0.633 AC: 21047 AN: 33234

American (AMR) AF: 0.145 AC: 6476 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 6942 AN: 26012

East Asian (EAS) AF: 0.322 AC: 12709 AN: 39522

South Asian (SAS) AF: 0.366 AC: 31383 AN: 85748

European-Finnish (FIN) AF: 0.220 AC: 11701 AN: 53210

Middle Eastern (MID) AF: 0.299 AC: 1716 AN: 5746

European-Non Finnish (NFE) AF: 0.232 AC: 255833 AN: 1104810

Other (OTH) AF: 0.282 AC: 16974 AN: 60096

GnomAD4 genome AF: 0.341 AC: 51853 AN: 151848 Hom.: 11186 Cov.: 32 AF XY: 0.339 AC XY: 25198 AN XY: 74232

African (AFR) AF: 0.613 AC: 25322 AN: 41320

American (AMR) AF: 0.209 AC: 3185 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3472

East Asian (EAS) AF: 0.337 AC: 1737 AN: 5152

South Asian (SAS) AF: 0.380 AC: 1831 AN: 4816

European-Finnish (FIN) AF: 0.228 AC: 2406 AN: 10572

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

European-Non Finnish (NFE) AF: 0.228 AC: 15471 AN: 67934

Other (OTH) AF: 0.321 AC: 676 AN: 2108

Alfa AF: 0.274 Hom.: 20404

Bravo AF: 0.350

Asia WGS AF: 0.370 AC: 1287 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	-0.29
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1741488; hg19: chr14-65245956; COSMIC: COSV67631360;