rs1555367318

Positions:

• chr14-64770878-CCCTCACCTGGG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001355436.2(SPTB):​c.5794_5798+6del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPTB NM_001355436.2 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.97

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-64770878-CCCTCACCTGGG-C is Pathogenic according to our data. Variant chr14-64770878-CCCTCACCTGGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 523359.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.5794_5798+6del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	27/36	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.5794_5798+6del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	27/36		NM_001355436.2	ENSP00000495909	P1
SPTB	ENST00000553938.5	c.1789_1793+6del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/18	1		ENSP00000451324
SPTB	ENST00000389720.4	c.5794_5798+6del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	27/32	5		ENSP00000374370
SPTB	ENST00000389722.7	c.5794_5798+6del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	26/35	2		ENSP00000374372	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555367318; hg19: chr14-65237596;