chr16-176733-C-A

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

Scores

6
12

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3O:1

Conservation

PhyloP100: -0.565
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]

Genome browser will be placed here

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
HBA1NM_000558.5 linkuse as main transcriptc.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
HBA1ENST00000320868.9 linkuse as main transcriptc.17C>A p.Ala6Asp missense_variant 1/31 NM_000558.5 ENSP00000322421 P1
HBA1ENST00000472694.1 linkuse as main transcriptn.36C>A non_coding_transcript_exon_variant 1/21
HBA1ENST00000397797.1 linkuse as main transcriptc.-31C>A 5_prime_UTR_variant 1/32 ENSP00000380899
HBA1ENST00000487791.1 linkuse as main transcript upstream_gene_variant 1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152136
Hom.:
0
Cov.:
28
FAILED QC
Gnomad AFR
AF:
0.00
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
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000973
AC:
14
AN:
1438688
Hom.:
0
Cov.:
29
AF XY:
0.0000112
AC XY:
8
AN XY:
714426
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000127
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152136
Hom.:
0
Cov.:
28
AF XY:
0.00
AC XY:
0
AN XY:
74316
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

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 submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMay 27, 2023In 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 submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesAug 16, 2022The 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 providedclinical testingNatera, Inc.Aug 31, 2021- -
HEMOGLOBIN J (TORONTO) Other:1
other, no assertion criteria providedliterature onlyOMIMJul 20, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
-0.010
CADD
Benign
7.5
DANN
Benign
0.73
DEOGEN2
Benign
0.14
T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.92
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.81
T
M_CAP
Uncertain
0.13
D
MetaRNN
Benign
0.19
T
MetaSVM
Uncertain
-0.18
T
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.2
N
REVEL
Uncertain
0.54
Sift
Benign
0.46
T
Sift4G
Benign
0.62
T
Vest4
0.26
MutPred
0.11
Loss of MoRF binding (P = 0.0116);
MVP
0.97
ClinPred
0.031
T
GERP RS
1.2
Varity_R
0.19
gMVP
0.69

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs34090856; hg19: chr16-226732; API