GeneBe

rs34353199

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PM4_Supporting

The NM_000558.5(HBA1):​c.184_186delAAG​(p.Lys62del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000667 in 149,886 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Consequence

HBA1
NM_000558.5 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.830

Publications

0 publications found
Variant links:
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]
HBA1 Gene-Disease associations (from GenCC):
  • alpha thalassemia spectrum
    Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
  • erythrocytosis, familial, 7
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • hemoglobin M disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Hb Bart's hydrops fetalis
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hemoglobin H disease
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • methemoglobinemia, alpha type
    Inheritance: AD Classification: LIMITED Submitted by: ClinGen
  • Heinz body anemia
    Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1
In a glycosylation_site N-linked (Glc) (glycation) lysine (size 0) in uniprot entity HBA_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000558.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBA1NM_000558.5 linkc.184_186delAAG p.Lys62del conservative_inframe_deletion Exon 2 of 3 ENST00000320868.9 NP_000549.1 P69905D1MGQ2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBA1ENST00000320868.9 linkc.184_186delAAG p.Lys62del conservative_inframe_deletion Exon 2 of 3 1 NM_000558.5 ENSP00000322421.5 P69905

Frequencies

GnomAD3 genomes
AF:
0.00000667
AC:
1
AN:
149886
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000247
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
AF:
0.00000667
AC:
1
AN:
149886
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
73064
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000247
AC:
1
AN:
40468
American (AMR)
AF:
0.00
AC:
0
AN:
15052
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3440
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5090
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4592
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10456
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67566
Other (OTH)
AF:
0.00
AC:
0
AN:
2002
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Nov 03, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.83
Mutation Taster
=36/64
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs34353199; hg19: chr16-227012; API