rs1555367318

Variant names:

• chr14-64770878-CCCTCACCTGGG-C
• rs1555367318
• NM_001355436.2:c.5794_5798+6delCCCAGGTGAGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001355436.2(SPTB):​c.5794_5798+6delCCCAGGTGAGG​(p.Pro1932fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTB NM_001355436.2 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97
• Publications: 0 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: Labcorp Genetics (formerly Invitae)
• elliptocytosis 3

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary elliptocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary spherocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 14-64770878-CCCTCACCTGGG-C is Pathogenic according to our data. Variant chr14-64770878-CCCTCACCTGGG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 523359.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.5794_5798+6delCCCAGGTGAGG	p.Pro1932fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 27 of 36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.5794_5798+6delCCCAGGTGAGG	p.Pro1932fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 27 of 36		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.1789_1793+6delCCCAGGTGAGG	p.Pro597fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 8 of 18	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.5794_5798+6delCCCAGGTGAGG	p.Pro1932fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 26 of 35	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.5794_5798+6delCCCAGGTGAGG	p.Pro1932fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 27 of 32	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hemolytic anemia Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555367318; hg19: chr14-65237596;