16-176736-A-G
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000558.5(HBA1):āc.20A>Gā(p.Asp7Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 28)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBA1
NM_000558.5 missense
NM_000558.5 missense
Scores
9
6
3
Clinical Significance
Conservation
PhyloP100: 5.07
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_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBA1 | NM_000558.5 | c.20A>G | p.Asp7Gly | 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.20A>G | p.Asp7Gly | missense_variant | 1/3 | 1 | NM_000558.5 | ENSP00000322421 | P1 | |
HBA1 | ENST00000472694.1 | n.39A>G | non_coding_transcript_exon_variant | 1/2 | 1 | |||||
HBA1 | ENST00000397797.1 | c.-28A>G | 5_prime_UTR_variant | 1/3 | 2 | ENSP00000380899 | ||||
HBA1 | ENST00000487791.1 | upstream_gene_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD3 genomes
Cov.:
28
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1433546Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 711574
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
AC:
0
AN:
1433546
Hom.:
Cov.:
28
AF XY:
AC XY:
0
AN XY:
711574
Gnomad4 AFR exome
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Gnomad4 SAS exome
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GnomAD4 genome Cov.: 28
GnomAD4 genome
Cov.:
28
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Erythrocytosis, familial, 7 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 1996 | - - |
alpha Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 21, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 06, 2020 | The Hb Swan River variant (HBA1: c.20A>G; p.Asp7Gly, also known as Asp6Gly when numbered from the mature protein, rs33986902) is reported in the literature in normal individuals, as well as an individual with erythrocytosis (Como 1989, Harano 1996, HbVar database and references therein). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartate at codon 7 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Isopropanol precipitation gives conflicting results, with one study suggesting slight instability and another report suggesting normal stability (Como 1989, Harano 1996). Due to limited information, the clinical significance of the Hb Swan River variant is uncertain at this time. References: HbVar link to Hb Swan River: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=9 Como PF et al. Hb Swan River [alpha 6(A4) Asp----Gly] initial identification in an Australian family. Hemoglobin. 1989;13(4):393-6. Harano T et al. HB Swan River [alpha 6(A4)ASP-->Gly] observed in a Japanese man. Hemoglobin. 1996 Feb;20(1):75-8. - |
HEMOGLOBIN SWAN RIVER Other:1
other, no assertion criteria provided | literature only | OMIM | Nov 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Pathogenic
D
Vest4
MutPred
Gain of MoRF binding (P = 0.0081);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at