chr14-64774392-C-T

Variant names:

• chr14-64774392-C-T
• rs1555367789
• NM_001355436.2:c.4973+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001355436.2(SPTB):​c.4973+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SPTB NM_001355436.2 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.35
• Publications: 1 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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 14-64774392-C-T is Pathogenic according to our data. Variant chr14-64774392-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 544813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPTB	NM_001355436.2	c.4973+5G>A		splice_region_variant, intron_variant	Intron 24 of 35	ENST00000644917.1	NP_001342365.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPTB	ENST00000644917.1	c.4973+5G>A		splice_region_variant, intron_variant	Intron 24 of 35		NM_001355436.2	ENSP00000495909.1
SPTB	ENST00000553938.5	c.968+5G>A		splice_region_variant, intron_variant	Intron 5 of 17	1		ENSP00000451324.1
SPTB	ENST00000389722.7	c.4973+5G>A		splice_region_variant, intron_variant	Intron 23 of 34	2		ENSP00000374372.3
SPTB	ENST00000389720.4	c.4973+5G>A		splice_region_variant, intron_variant	Intron 24 of 31	5		ENSP00000374370.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434202 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 711050

African (AFR) AF: 0.00 AC: 0 AN: 32930

American (AMR) AF: 0.00 AC: 0 AN: 41834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25626

East Asian (EAS) AF: 0.00 AC: 0 AN: 38440

South Asian (SAS) AF: 0.00 AC: 0 AN: 82362

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5078

European-Non Finnish (NFE) AF: 9.10e-7 AC: 1 AN: 1099374

Other (OTH) AF: 0.00 AC: 0 AN: 59260

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Sep 24, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 23 of the SPTB gene. It does not directly change the encoded amino acid sequence of the SPTB protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with spherocytosis (PMID: 29572776, 31807509; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 544813). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SPTB c.4973+5G>A variant (rs1555367789) is reported in the literature in three individuals affected with hereditary spherocytosis (Mansour-Hendili 2020, Wang 2018, Xue 2019), including once as a de novo mutation. This variant is also reported in ClinVar (Variation ID: 544813). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be likely pathogenic. References: Mansour-Hendili L et al. Exome sequencing for diagnosis of congenital hemolytic anemia. Orphanet J Rare Dis. 2020 Jul 8. PMID: 32641076. Wang R et al. Exome sequencing confirms molecular diagnoses in 38 Chinese families with hereditary spherocytosis. Sci China Life Sci. 2018 Aug. PMID: 29572776. Xue J et al. Clinical utility of targeted gene enrichment and sequencing technique in the diagnosis of adult hereditary spherocytosis. Ann Transl Med. 2019 Oct. PMID: 31807509. -

Dec 18, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4_moderate, PM2, PP3, PP5 -

Hereditary spherocytosis type 2 Pathogenic:1

Feb 27, 2018

Department of Genetic, Henri Mondor Hospital, Assistance Publique des Hôpitaux de Paris

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	33
DANN	Benign	0.63
PhyloP100		3.4
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: -21
DS_DL_spliceai		0.38		Position offset: 5

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

Other links and lift over

dbSNP: rs1555367789; hg19: chr14-65241110;