11-5225592-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000518.5(HBB):c.*6C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000518.5 3_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135858
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461770Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727200
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
beta Thalassemia Pathogenic:1Other:1
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not provided Pathogenic:1
This variant has been observed in individual(s) with autosomal recessive beta-thalassemia (PMID: 1777603, 9792288). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant occurs in a non-coding region of the HBB gene. It does not change the encoded amino acid sequence of the HBB protein. This variant is present in population databases (rs34809925, gnomAD 0.0009%). This variant is also known as term +6C>G or +1480C>G. ClinVar contains an entry for this variant (Variation ID: 393707). Studies have shown that this variant does not significantly alter or has an unclear effect on HBB gene expression (PMID: 9792288, 22734587). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Beta thalassemia intermedia Pathogenic:1
Variant summary: HBB c.*6C>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 4e-06 in 251382 control chromosomes. This frequency is not higher than the estimated maximum expected for a pathogenic variant in HBB causing Beta Thalassemia Intermedia (0.011), allowing no conclusion about variant significance. The variant c.*6C>G (aka. +1480T>G) has been reported in the literature in multiple individuals affected with Beta Thalassemia Intermedia (e.g. Maragoudaki_1998, Jankovic_1991, Aldemir_2014). These data indicate that the variant is very likely to be associated with disease. Publications also reported in vitro experimental evidence evaluating the variant impact, and demonstrated about 20-40% reduction in mRNA levels associated with variant compared to normal beta-globin alleles (Maragoudaki_1998, Sgourou_2002), while another study showed a slightly higher (1.1 fold) levels of expression than WT (Hino_2012). One reputable database has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at