16-176733-C-A
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000558.5(HBA1):c.17C>A(p.Ala6Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A6P) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., cov: 28)
Exomes 𝑓: 0.0000097 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBA1
NM_000558.5 missense
NM_000558.5 missense
Scores
6
12
Clinical Significance
Conservation
PhyloP100: -0.565
Genes affected
HBA1 (HGNC:4823): (hemoglobin subunit alpha 1) 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 Likely_benign. Variant got -2 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.19086808).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBA1 | NM_000558.5 | c.17C>A | p.Ala6Asp | missense_variant | 1/3 | ENST00000320868.9 | NP_000549.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBA1 | ENST00000320868.9 | c.17C>A | p.Ala6Asp | missense_variant | 1/3 | 1 | NM_000558.5 | ENSP00000322421 | P1 | |
HBA1 | ENST00000472694.1 | n.36C>A | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
HBA1 | ENST00000397797.1 | c.-31C>A | 5_prime_UTR_variant | 1/3 | 2 | ENSP00000380899 | ||||
HBA1 | ENST00000487791.1 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152136Hom.: 0 Cov.: 28 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000973 AC: 14AN: 1438688Hom.: 0 Cov.: 29 AF XY: 0.0000112 AC XY: 8AN XY: 714426
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GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152136Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 27, 2023 | In the published literature, this variant has been reported in individuals with normal hematological characterizations (PMID: 5870555 (1965), 5169069 (1971)), as well as individuals with diabetes (PMID: 25109349 (2014)), and individuals with hypochromic microcytic anemia (PMID: 23402770 (2013)). This variant is reported as having normal stability and normal cell morphology (PMID: 5870555 (1965), 5169069 (1971)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 16, 2022 | The Hb J Toronto variant (HBA1 c.17C>A; p.Ala6Asp, also known as or Ala5Asp when numbered from the mature protein, rs34090856, HbVarID: 3) is reported in the literature in the heterozygous state and in the compound heterozygous state with the 3.7kb deletion in individuals without any significant hematological symptoms (see HbVar and references therein, Mahdavi 2012, Van Laer 2014). Aberrant HbA1c measurements have been reported in several individuals with this variant (Van Laer 2014). This variant is reported in ClinVar (Variation ID: 15765), and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The alanine at codon 6 is weakly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.544). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Mahdavi M et al. Report of haemoglobin J-Toronto and alpha thalassemia in a family from North of Iran. J Pak Med Assoc. 2012 Apr;62(4):396-8. PMID: 22755290. Van Laer C et al. Aberrant glycated haemoglobin (HbA1c) results leading to haemoglobinopathy diagnosis in four Belgian patients. Acta Clin Belg. 2014 Dec;69(6):456-9. PMID: 25109349. - |
alpha Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2021 | - - |
HEMOGLOBIN J (TORONTO) Other:1
other, no assertion criteria provided | literature only | OMIM | Jul 20, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Vest4
MutPred
Loss of MoRF binding (P = 0.0116);
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at