rs33918778
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000518.5(HBB):c.123G>T(p.Arg41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
HBB
NM_000518.5 missense
NM_000518.5 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 1.96
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 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, 0.968
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.123G>T | p.Arg41Ser | missense_variant | 2/3 | ENST00000335295.4 | NP_000509.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.123G>T | p.Arg41Ser | missense_variant | 2/3 | 1 | NM_000518.5 | ENSP00000333994 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD3 genomes
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152142
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32
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GnomAD4 exome Cov.: 36
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 09, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 20, 2023 | The Hb Austin variant (HBB: c.123G>T; p.Arg41Ser, also known as Arg40Ser when numbered from the mature protein, rs33918778, HbVar ID: 311) is reported in the literature in the heterozygous state in multiple individuals of Mexican ancestry with no clinical symptoms (HbVar and references therein, Racsa 2014, Moo-Penn 1977). However, the phenotype of this variant in the presence of other alpha globin variants is unknown. Functional characterization indicate that the variant hemoglobin has normal Bohr effect, increased oxygen affinity, reduced cooperativity, and found to dissociate into oxyHb dimers (HbVar and references therein). The c.123G>T variant is reported in ClinVar (Variation ID: 439134). It is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.9). Due to the limited information regarding this variant, its clinical significance is uncertain at this time. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Racsa LD et al. Beta-Globin gene sequencing of hemoglobin Austin revises the historically reported electrophoretic migration pattern. Arch Pathol Lab Med. 2014 Jun;138(6):819-22. PMID: 24878022. Moo-Penn WF et al. Hemoglobins Austin and Waco: two hemoglobins with substitutions in the alpha 1 beta 2 contact region. Arch Biochem Biophys. 1977 Feb;179(1):86-94. doi: 10.1016/0003-9861(77)90089-3. PMID: 14597. - |
beta Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 28, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;.;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D
Sift4G
Uncertain
D;.;.;.
Polyphen
D;D;.;.
Vest4
MutPred
Gain of disorder (P = 0.0898);Gain of disorder (P = 0.0898);Gain of disorder (P = 0.0898);Gain of disorder (P = 0.0898);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at