14-64775349-T-G

Position:

• chr14-64775349-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001355436.2(SPTB):​c.4618A>C​(p.Arg1540=) 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:6
• Conservation: PhyloP100: 1.04

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 257122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64775349-T-G is described in Lovd as [Benign]. Variant chr14-64775349-T-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00494 (7212/1461078) while in subpopulation NFE AF= 0.00591 (6575/1111658). AF 95% confidence interval is 0.00579. There are 30 homozygotes in gnomad4_exome. There are 3516 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTB	NM_001355436.2	c.4618A>C	p.Arg1540=	synonymous_variant	23/36	ENST00000644917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTB	ENST00000644917.1	c.4618A>C	p.Arg1540=	synonymous_variant	23/36		NM_001355436.2	P1
SPTB	ENST00000553938.5	c.613A>C	p.Arg205=	synonymous_variant	4/18	1
SPTB	ENST00000389722.7	c.4618A>C	p.Arg1540=	synonymous_variant	22/35	2		P1
SPTB	ENST00000389720.4	c.4618A>C	p.Arg1540=	synonymous_variant	23/32	5

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

GnomAD3 exomes AF: 0.00308 AC: 768 AN: 249650 Hom.: 0 AF XY: 0.00323 AC XY: 437 AN XY: 135132

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 SAS exome AF: 0.00170

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

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00220

Gnomad4 FIN exome AF: 0.00218

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00381

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

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00575

Gnomad4 OTH AF: 0.000945

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SPTB: BP4, BP7, BS2 -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.62
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs61989884; hg19: chr14-65242067;