rs33915217

Positions:

• chr11-5226925-C-A
• chr11-5226925-C-G
• chr11-5226925-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000518.5(HBB):​c.92+5G>T variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,918 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.72

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-5226925-C-A is Pathogenic according to our data. Variant chr11-5226925-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 15448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226925-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.92+5G>T		splice_donor_5th_base_variant, intron_variant		ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.92+5G>T		splice_donor_5th_base_variant, intron_variant		1	NM_000518.5	ENSP00000333994	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251204 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135754

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459918 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726420

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change falls in intron 1 of the HBB gene. It does not directly change the encoded amino acid sequence of the HBB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs33915217, gnomAD 0.0009%). This variant has been observed in individuals with beta-thalassemia (PMID: 2439149). ClinVar contains an entry for this variant (Variation ID: 15448). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in alternate splicing and introduces a premature termination codon (PMID: 2439149). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.92+5G nucleotide in the HBB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 2200760, 3021139, 23162295, 27263053). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	The HBB c.92+5G>T variant (rs33915217, HbVar ID: 825), also known as IVS-I-5 (G->T), has been reported in the homozygous or compound heterozygous state in several individuals affected with beta(+) thalassemia (Atweh 1987, HbVar database and references therein). Functional studies indicate that the variant causes aberrant splicing of the HBB transcript and reduction of full-length mRNA (Atweh 1987). The variant is listed as pathogenic in ClinVar (Variation ID: 15448), and observed once in the Genome Aggregation Database (1/251204 alleles). Consistent with functional studies, computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, the variant c.92+5G>T is classified as pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html Atweh G et al. A new mutation in IVS-1 of the human beta globin gene causing beta thalassemia due to abnormal splicing. Blood. 1987; 70(1):147-51. PMID: 2439149. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348723, 22975760, 25525159, 9163586, 2577233, 2439149, 33092414) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 07, 2016	- -

beta Thalassemia Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Sep 03, 2015	- -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -

Beta-thalassemia major Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Beta-plus-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1989

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 21
DS_DL_spliceai		0.73		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs33915217; hg19: chr11-5248155;