rs41407250
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PP3_StrongBP6_Very_Strong
The NM_000558.5(HBA1):āc.49A>Gā(p.Lys17Glu) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K17M) has been classified as Uncertain significance.
Frequency
Genomes: š 0.0 ( 0 hom., cov: 28)
Exomes š: 0.0000042 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBA1
NM_000558.5 missense
NM_000558.5 missense
Scores
7
5
6
Clinical Significance
Conservation
PhyloP100: 4.90
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 -4 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.986
BP6
?
Variant 16-176765-A-G is Benign according to our data. Variant chr16-176765-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 15746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBA1 | NM_000558.5 | c.49A>G | p.Lys17Glu | missense_variant | 1/3 | ENST00000320868.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBA1 | ENST00000320868.9 | c.49A>G | p.Lys17Glu | missense_variant | 1/3 | 1 | NM_000558.5 | P1 | |
HBA1 | ENST00000472694.1 | n.68A>G | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA1 | ENST00000487791.1 | n.18A>G | non_coding_transcript_exon_variant | 1/2 | 1 | ||||
HBA1 | ENST00000397797.1 | c.-2+3A>G | splice_donor_region_variant, intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 150228Hom.: 0 Cov.: 28 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000417 AC: 6AN: 1437400Hom.: 0 Cov.: 27 AF XY: 0.00000280 AC XY: 2AN XY: 713834
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GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 150228Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 73186
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ClinVar
Significance: Likely benign
Submissions summary: Benign:3Other:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2023 | Variant summary: HBA1 c.49A>G (p.Lys17Glu) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6e-06 in 166854 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.49A>G variant (aka Hemoglobin I, Hb I Burlington), is a known hemoglobin variant with altered electrophoretic mobility, and was reported in several asymptomatic heterozygotes, who had no hematological abnormalities (e.g. Saito_1984, Fleming_1978, Arya_2009, Lin_2013). To our knowledge, no homozygous occurrences, or compound heterozygotes with pathogenic HBA1 (or HBA2) variants were reported. The variant was reported in combination with a pathogenic HBB variant, however this individual was only mildly anemic, with a mild hypochromia and microcytosis, which are consistent with the beta-thalassemia carrier state (Arya_2009). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the oxygen equilibrium and kinetic properties of hemoglobin I were indistinguishable from those of the WT (McDonald_1974). Studies also reported that the variant might (slightly) interfere with the measurement of glycosylated hemoglobin (HbA1c) that laboratories should be aware of to avoid mismanagement of individuals carrying this variant (Arya_2009, Zechmeister_2022). The following publications have been ascertained in the context of this evaluation (PMID: 4444049, 6085353, 740406, 19234704, 23806067, 35378091, 5480848). Two submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 09, 2016 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 02, 2022 | - - |
HEMOGLOBIN I (TEXAS) Other:1
other, no assertion criteria provided | literature only | OMIM | May 10, 2018 | - - |
HEMOGLOBIN I (SKAMANIA) Other:1
other, no assertion criteria provided | literature only | OMIM | May 10, 2018 | - - |
HEMOGLOBIN I (BURLINGTON) Other:1
other, no assertion criteria provided | literature only | OMIM | May 10, 2018 | - - |
HEMOGLOBIN I Other:1
other, no assertion criteria provided | literature only | OMIM | May 10, 2018 | - - |
HEMOGLOBIN I (PHILADELPHIA) Other:1
other, no assertion criteria provided | literature only | OMIM | May 10, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Uncertain
D
Vest4
MutPred
Loss of MoRF binding (P = 0.0034);
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