11-5226954-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP6

The NM_000518.5(HBB):ā€‹c.68A>Gā€‹(p.Glu23Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E23K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

3
8
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1O:1

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5226954-T-G is described in Lovd as [Pathogenic].
BP6
Variant 11-5226954-T-C is Benign according to our data. Variant chr11-5226954-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15178.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HBBNM_000518.5 linkc.68A>G p.Glu23Gly 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>G p.Glu23Gly missense_variant Exon 1 of 3 1 NM_000518.5 ENSP00000333994.3 P68871

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461524
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727106
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Uncertain:1Benign:1
Dec 07, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant is associated with normal clinical presentation when in heterozygosity (PMIDs: 3623978 (1987) and 23806067 (2013)). It has also been identified as a common variant in China, seen in a subject with reduced mean corpuscular volume levels from a routine blood analysis, and among subjects with hemoglobin disorders (PMIDs: 29626415 (2018), 26950205 (2016), and 25849334 (2015)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jul 22, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Hb G-Taipei variant (HBB: c.68A>G; p.Glu23Gly, also known as Glu22Gly when numbered from the mature protein, rs33936254, HbVar ID: 265) is reported in the heterozygous state in asymptomatic individuals with normal hematological parameters (Lin 2013, Zhang 2015, Zhang 2017, HbVar and references therein). This variant has not been reported with a pathogenic variant on the opposite chromosome, although, other variants at this codon (Glu22Ala, Glu22Gln) exhibit no clinical symptoms when found with a beta0 pathogenic variant in trans (Agrawal 2007, Koseler 2013, Rohe 1973). The Hb G-Taipei variant is listed in ClinVar (Variation ID: 15178). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.59). Based on available information, the Hb G-Taipei variant is considered to be likely benign. References: HbVar database link: https://globin.bx.psu.edu/hbvar/menu.html Agrawal M et al. Compound heterozygosity of Hb D(Iran) (beta(22) Glu-->Gln) and beta(0)-thalassemia (619 bp-deletion) in India. Eur J Haematol. 2007 Sep;79(3):248-50. PMID: 17655708. 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. PMID: 23001606. Lin M et al. Molecular epidemiological survey of hemoglobinopathies in the Wuxi region of Jiangsu Province, eastern China. Hemoglobin. 2013;37(5):454-66. PMID: 23806067. Rohe R et al. Hemoglobin D Iran alpha A2 beta 22 2-Glu leads to Gln in association with thalassemia. Blood. 1973 Sep;42(3):455-62. PMID: 4725603. Zhang J et al. Genetic heterogeneity of the B-globin gene in various geographic populations of Yunnan in southwestern China. PLoS One. 2015 Apr 7;10(4):e0122956. PMID: 25849334. Zhang XM et al. Effects of hemoglobin variants HbJ Bangkok, HbE, HbG Taipei, and HbH on analysis of glycated hemoglobin via ion-exchange high-performance liquid chromatography. J Clin Lab Anal. 2017 Apr 13. PMID: 28407371. -

HEMOGLOBIN G (TAIPEI) Other:1
Dec 12, 2017
OMIM
Significance: other
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.041
T;T;.;T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.58
FATHMM_MKL
Benign
0.53
D
LIST_S2
Benign
0.25
.;T;T;T
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.60
D;D;D;D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Pathogenic
3.3
M;M;.;.
PrimateAI
Benign
0.47
T
PROVEAN
Uncertain
-3.6
D;.;.;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0060
D;.;.;D
Sift4G
Uncertain
0.037
D;.;.;.
Polyphen
0.0010
B;B;.;.
Vest4
0.86
MutPred
0.63
Gain of catalytic residue at V24 (P = 0.0732);Gain of catalytic residue at V24 (P = 0.0732);Gain of catalytic residue at V24 (P = 0.0732);Gain of catalytic residue at V24 (P = 0.0732);
MVP
0.91
MPC
0.056
ClinPred
0.73
D
GERP RS
2.8
Varity_R
0.40
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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