rs35619054
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000518.5(HBB):c.146_147insATCT(p.Thr51ValfsTer4) variant causes a frameshift 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L49L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBB
NM_000518.5 frameshift
NM_000518.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.66
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 228 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-5226745-C-CAGAT is Pathogenic according to our data. Variant chr11-5226745-C-CAGAT is described in ClinVar as [Pathogenic]. Clinvar id is 439135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.146_147insATCT | p.Thr51ValfsTer4 | frameshift_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.146_147insATCT | p.Thr51ValfsTer4 | frameshift_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3AN: 1461878Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
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3
AN:
1461878
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Cov.:
36
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AC XY:
2
AN XY:
727246
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
beta Thalassemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 12, 2020 | Variant summary: HBB c.143_146dupATCT (p.Thr51ValfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251424 control chromosomes (gnomAD). c.143_146dupATCT [also known as CD 47/48 (+ATCT) and as c.146_147insATCT] has been reported in the literature, in the compound heterozygous and homozygous states, in multiple individuals affected with Beta Thalassemia (e.g. Garewal_1994, Jain_1994, Sharma_2010, Hoppe_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 439135). This variant is also known as insertion of 4 nucleotides (ATCT) at codon 48, codons 47/48 (+ATCT). This premature translational stop signal has been observed in individual(s) with beta thalassemia (PMID: 8081396). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr51Valfs*4) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 16, 2023 | The HBB c.143_146dup (p.Thr51Valfs*4) frameshift variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with beta thalassemia (PMID: 8081396 (1994), 8199027 (1994), 7558874 (1995), 20132300 (2010), 23590658 (2013)). Based on the available information, this variant is classified as pathogenic. - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at