chr14-64749402-C-T

Variant names:

• chr14-64749402-C-T
• rs57421986
• NM_001355436.2:c.6891G>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.6891G>A​(p.Ala2297Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,607,956 control chromosomes in the GnomAD database, including 5,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1373 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3905 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.40
• Publications: 8 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]

PLEKHG3 (HGNC:20364): (pleckstrin homology and RhoGEF domain containing G3) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-64749402-C-T is Benign according to our data. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64749402-C-T is described in CliVar as Benign. Clinvar id is 257137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.6891G>A	p.Ala2297Ala	synonymous_variant	Exon 36 of 36	ENST00000644917.1	NP_001342365.1
PLEKHG3	NM_001308147.2	c.*5699C>T		3_prime_UTR_variant	Exon 17 of 17	ENST00000247226.13	NP_001295076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.6891G>A	p.Ala2297Ala	synonymous_variant	Exon 36 of 36		NM_001355436.2	ENSP00000495909.1
PLEKHG3	ENST00000247226.13	c.*5699C>T		3_prime_UTR_variant	Exon 17 of 17	1	NM_001308147.2	ENSP00000247226.8

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16180 AN: 152122 Hom.: 1368 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0437

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0606

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0627

Gnomad OTH AF: 0.0890

GnomAD2 exomes AF: 0.0667 AC: 16191 AN: 242730 AF XY: 0.0649

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.0252

Gnomad ASJ exome AF: 0.0332

Gnomad EAS exome AF: 0.0334

Gnomad FIN exome AF: 0.0953

Gnomad NFE exome AF: 0.0610

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0659 AC: 95933 AN: 1455716 Hom.: 3905 Cov.: 32 AF XY: 0.0654 AC XY: 47356 AN XY: 724318

African (AFR) AF: 0.238 AC: 7964 AN: 33462

American (AMR) AF: 0.0271 AC: 1210 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.0332 AC: 867 AN: 26088

East Asian (EAS) AF: 0.0427 AC: 1696 AN: 39680

South Asian (SAS) AF: 0.0630 AC: 5433 AN: 86186

European-Finnish (FIN) AF: 0.0962 AC: 4619 AN: 48004

Middle Eastern (MID) AF: 0.0381 AC: 219 AN: 5750

European-Non Finnish (NFE) AF: 0.0627 AC: 69683 AN: 1111596

Other (OTH) AF: 0.0704 AC: 4242 AN: 60296

GnomAD4 genome AF: 0.107 AC: 16219 AN: 152240 Hom.: 1373 Cov.: 32 AF XY: 0.106 AC XY: 7915 AN XY: 74434

African (AFR) AF: 0.226 AC: 9390 AN: 41522

American (AMR) AF: 0.0437 AC: 668 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.0367 AC: 190 AN: 5180

South Asian (SAS) AF: 0.0604 AC: 292 AN: 4832

European-Finnish (FIN) AF: 0.103 AC: 1098 AN: 10610

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0627 AC: 4264 AN: 68006

Other (OTH) AF: 0.0881 AC: 186 AN: 2112

Alfa AF: 0.0697 Hom.: 500

Bravo AF: 0.106

Asia WGS AF: 0.0650 AC: 227 AN: 3478

EpiCase AF: 0.0593

EpiControl AF: 0.0566

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 16, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.7
DANN	Benign	0.92
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs57421986; hg19: chr14-65216120; COSMIC: COSV55981264;