11-5226954-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

The NM_000518.5(HBB):ā€‹c.68A>Cā€‹(p.Glu23Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E23G) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

2
6
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:3O:4

Conservation

PhyloP100: 1.78
Variant links:
Genes affected
HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5226955-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.68A>C p.Glu23Ala missense_variant Exon 1 of 3 ENST00000335295.4 NP_000509.1 P68871D9YZU5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HBBENST00000335295.4 linkc.68A>C p.Glu23Ala missense_variant Exon 1 of 3 1 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251294
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135798
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461520
Hom.:
0
Cov.:
33
AF XY:
0.00000688
AC XY:
5
AN XY:
727102
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:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152182
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
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
Bravo
AF:
0.00000756
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2Benign:3Other:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 10, 2024The Hb G-Coushatta variant (HBB: c.68A>C; p.Glu23Ala, also known as Glu22Ala when numbered from the mature protein, rs33936254, HbVar ID: 266) is reported in the heterozygous state in asymptomatic individuals (Blackwell 1967, HbVar database and references therein), and does not exacerbate clinical or hematological symptoms when found in trans to a pathogenic HBB variant (Koseler 2013, Perera 2015). The Hb G-Coushatta variant is reported in ClinVar (Variation ID: 15171), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamic acid at codon 23 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.566). Based on available information, the Hb G-Coushatta variant is considered to be likely benign. REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Blackwell R et al. Hemoglobin variants in Koreans: hemoglobin G Taegu. Science. 1967 158(3804):1056-7. Koseler A et al. Molecular studies on the origin of the Hb G-Coushatta mutation in Denizli province of Turkey. Biochem Genet. 2013 51(1-2):71-5. Perera PS et al. Rare hemoglobin variants: Hb G-Szuhu (HBB: c.243C>G), Hb G-Coushatta (HBB: c.68A>C) and Hb Mizuho (HBB: c.206T>C) in Sri Lankan families. Hemoglobin. 2015;39(1):62-5. -
Pathogenic, flagged submissionclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMay 19, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 11, 2023In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as Hb G-Coushatta; This variant is associated with the following publications: (PMID: 23001606, 9048934, 34426522, 6033745, 29717566, 31553106, 19429541, 25572187, 6021187, 3115700, 18619001, 23806067, 5658717, 30568544, 34766575, 5791015, 31300739, 37188672, 14081243, 721611, 2703366, 28865746, 10081986) -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 15, 2024The HBB c.68A>C (p.Glu23Ala) variant has been reported in the published literature in individuals, both heterozygous and homozygous, with normal clinical presentation ((HbVar http://globin.bx.psu.edu/, PMID: 27408413 (2016), and Ann Clin Case Rep (2017) 2:1353). The variant has also been reported in individuals with beta thalassemia and/or hemoglobin disorders (PMIDs: 23001606 (2013), 25849334 (2015), 37188672 (2023), and Quest internal patients). The frequency of this variant in the general population, 0.000008 (2/251294 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 21, 2025Variant summary: HBB c.68A>C (p.Glu23Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 676170 control chromosomes (gnomAD and publications). This frequency is not significantly higher than estimated for a pathogenic variant in HBB causing Hemoglobinopathy (8.4e-05 vs 0.011), allowing no conclusion about variant significance. c.68A>C has been reported in the literature in healthy Native American, East Asian, Turkish, Egyptian, and Sri Lankan individuals in the heterozygous or homozygous state, suggesting that the variant is benign (e.g. Schneider_1964, Ohba_1978, Cao_1987, Li_1990, Hergersberg_2008, HbVar database). It has also been found to co-occur in cis and in trans with pathogenic beta-thalassemia variants (e.g. c.93-21G>A, IVS-1-1, G>A, and IVS-I-5) in patients, however in these cases it was believed to have little to no clinical impact (e.g. Hergersberg_2008, Koseler_2013, Perera_2015) . These data indicate that the variant is unlikely to be associated with disease. Additionally, a functional study has shown the variant to have normal oxygen equilibrium characteristics, and heat denaturation and isopropanol tests on hemolysates did not reveal instability of the hemoglobin, suggesting that the variant has a neutral effect on protein function (Ohba_1978). The following publications have been ascertained in the context of this evaluation (PMID: 18523401, 5791015, 5658717, 3115700, 2703366, 9048934, 19429541, 18619001, 6859036, 23001606, 2265836, 10081986, 23806067, 721611, 25572187, 18403562, 31553106, 14081243, 37188672, 27265760). ClinVar contains an entry for this variant (Variation ID: 15171). Based on the evidence outlined above, the variant was classified as likely benign. -
beta Thalassemia Benign:1
Benign, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
HEMOGLOBIN G (COUSHATTA) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -
HEMOGLOBIN G (HSIN-CHU) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -
HEMOGLOBIN G (TAEGU) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -
HEMOGLOBIN G (SASKATOON) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.051
BayesDel_addAF
Pathogenic
0.18
D
BayesDel_noAF
Pathogenic
0.21
CADD
Benign
14
DANN
Benign
0.94
DEOGEN2
Benign
0.038
T;T;.;T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.67
FATHMM_MKL
Benign
0.51
D
LIST_S2
Benign
0.071
.;T;T;T
M_CAP
Uncertain
0.24
D
MetaRNN
Uncertain
0.43
T;T;T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
1.3
L;L;.;.
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.5
N;.;.;D
REVEL
Uncertain
0.57
Sift
Benign
0.082
T;.;.;T
Sift4G
Benign
0.34
T;.;.;.
Polyphen
0.0
B;B;.;.
Vest4
0.67
MutPred
0.67
Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);Loss of catalytic residue at E23 (P = 0.0407);
MVP
0.91
MPC
0.043
ClinPred
0.082
T
GERP RS
2.8
Varity_R
0.22
gMVP
0.67

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: rs33936254; hg19: chr11-5248184; API