chr16-173008-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong
The NM_000517.6(HBA2):c.95+1G>A variant causes a splice donor, intron change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000517.6 splice_donor, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.95+1G>A | splice_donor_variant, intron_variant | Intron 1 of 2 | 1 | NM_000517.6 | ENSP00000251595.6 | |||
HBA2 | ENST00000484216.1 | c.62+1G>A | splice_donor_variant, intron_variant | Intron 1 of 1 | 1 | ENSP00000495899.1 | ||||
HBA2 | ENST00000482565.1 | n.115G>A | non_coding_transcript_exon_variant | Exon 1 of 2 | 1 | |||||
HBA2 | ENST00000397806.1 | c.-2+50G>A | intron_variant | Intron 1 of 2 | 2 | ENSP00000380908.1 |
Frequencies
GnomAD3 genomes Cov.: 3
GnomAD3 exomes AF: 0.0000181 AC: 1AN: 55352Hom.: 0 AF XY: 0.0000358 AC XY: 1AN XY: 27898
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000902 AC: 4AN: 443356Hom.: 1 Cov.: 0 AF XY: 0.0000171 AC XY: 4AN XY: 233618
GnomAD4 genome Cov.: 3
ClinVar
Submissions by phenotype
not specified Pathogenic:1
The HBA2 c.95+1G>A variant (rs63750158) is reported in the literature in a sickle cell carrier with microcytic anemia and reduced Hb S levels (Waye 2009). An analogous c.95+1G>A variant in the HBA1 gene has also been reported in several individuals with Hb H disease that also carried the --SEA deletion (Harteveld 2000, Viprakasit 2014). The HBA2 c.95+1G>A variant is reported in ClinVar (Variation ID: 439126), and it is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 1, and RNA studies indicate this leads to splicing at a cryptic splice donor, deletion of 49 nucleotides, and introduction of a premature stop codon (Harteveld 2000, Qadah 2014). Based on available information, this variant is considered to be pathogenic. References: Harteveld CL et al. alpha-thalassaemia as a result of a novel splice donor site mutation of the alpha1-globin gene. Br J Haematol. 2000 Sep;110(3):694-8. Qadah T et al. In vitro characterization of the a-thalassemia point mutation HBA2:c.95+1G>A [IVS-I-1(G>A) (a2)]. Hemoglobin. 2012;36(1):38-46. Viprakasit V et al. Clinical presentation and molecular identification of four uncommon alpha globin variants in Thailand. Initiation codon mutation of a2-globin Gene (HBA2:c.1delA), donor splice site mutation of a1-globin gene (IVSI-1, HBA1:c.95 + 1G>A), hemoglobin Queens Park/Chao Pra Ya (HBA1:c.98T>A) and hemoglobin Westmead (HBA2:c.369C>G). Acta Haematol. 2014;131(2):88-94. Waye JS et al. alpha-Thalassemia caused by two novel splice mutations of the alpha2-globin gene: IVS-I-1 (G>A and G>T). Hemoglobin. 2009;33(6):519-22. -
alpha Thalassemia Pathogenic:1
- -
not provided Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at