rs33918778
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R41K) has been classified as Likely benign.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.123G>T | p.Arg41Ser | missense_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.123G>T | p.Arg41Ser | missense_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 36
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152142Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
not provided Uncertain:2
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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 09, 2020 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at