rs12433436

Positions:

• chr14-64793101-G-A
• chr14-64793101-G-C

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.2562C>T​(p.Phe854Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,076 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: SPTB NM_001355436.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0190

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=-0.49).
• BP6: Variant 14-64793101-G-A is Benign according to our data. Variant chr14-64793101-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 257103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64793101-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.019 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00163 (248/152316) while in subpopulation EAS AF= 0.0168 (87/5176). AF 95% confidence interval is 0.014. There are 2 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.2562C>T	p.Phe854Phe	synonymous_variant	14/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.2562C>T	p.Phe854Phe	synonymous_variant	14/36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000389722.7	c.2562C>T	p.Phe854Phe	synonymous_variant	13/35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.2562C>T	p.Phe854Phe	synonymous_variant	14/32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0168

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00289 AC: 725 AN: 251054 Hom.: 5 AF XY: 0.00237 AC XY: 322 AN XY: 135814

Gnomad AFR exome AF: 0.000928

Gnomad AMR exome AF: 0.00925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0189

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00110 AC: 1606 AN: 1461760 Hom.: 18 Cov.: 32 AF XY: 0.00108 AC XY: 784 AN XY: 727178

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00968

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152316 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74470

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0168

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00131 Hom.: 1

Bravo AF: 0.00223

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Elliptocytosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Spherocytosis, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.1
DANN	Benign	0.67

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: rs12433436; hg19: chr14-65259819; COSMIC: COSV101072303;