rs587776827
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_000517.6(HBA2):c.301-1G>A variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000000686 in 1,457,858 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★).
Frequency
Genomes: not found (cov: 25)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
HBA2
NM_000517.6 splice_acceptor
NM_000517.6 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.58
Genes affected
HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
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 16-173471-G-A is Pathogenic according to our data. Variant chr16-173471-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15668.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA2 | NM_000517.6 | c.301-1G>A | splice_acceptor_variant | ENST00000251595.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA2 | ENST00000251595.11 | c.301-1G>A | splice_acceptor_variant | 1 | NM_000517.6 | P1 | |||
ENST00000702607.1 | downstream_gene_variant |
Frequencies
GnomAD3 genomes ? Cov.: 25
GnomAD3 genomes
?
Cov.:
25
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457858Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 725062
GnomAD4 exome
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1
AN:
1457858
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Cov.:
33
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AC XY:
1
AN XY:
725062
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 25
GnomAD4 genome
?
Cov.:
25
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
alpha Thalassemia Pathogenic:1
Pathogenic, no assertion criteria provided | curation | The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Nov 25, 2019 | - - |
Hemoglobin H disease, nondeletional Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2001 | - - |
alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 12, 2021 | - - |
HEMOGLOBIN CLINICO-MADRID Other:1
other, no assertion criteria provided | literature only | OMIM | Mar 28, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 9
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at