chr11-5226988-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4
The NM_000518.5(HBB):c.34G>A(p.Val12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,613,042 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V12D) has been classified as Uncertain significance.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.34G>A | p.Val12Ile | missense_variant | 1/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.34G>A | p.Val12Ile | missense_variant | 1/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251232Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135770
GnomAD4 exome AF: 0.0000541 AC: 79AN: 1460830Hom.: 0 Cov.: 33 AF XY: 0.0000454 AC XY: 33AN XY: 726820
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2018 | This sequence change replaces valine with isoleucine at codon 12 of the HBB protein (p.Val12Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs33974228, ExAC 0.01%). This variant has been observed in individuals with HBB-related conditions (PMID: 19727720) and has been observed in healthy individuals as well (PMID: 1610915, 3623977). This variant is known as Hb Hamilton in the literature. ClinVar contains an entry for this variant (Variation ID: 15189, 15596). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 23, 2018 | The Hb Hamilton variant (HBB: c.34G>A; Val11Ile) (rs33974228) is not associated with clinical symptoms in heterozygous carriers and demonstrates normal function and relative stability (see HbVar database link and references therein). However, its phenotype when found with other pathogenic globin variants is unknown. Hb Hamilton does not affect the net charge and thus is not detectable by HPLC (see HbVar database link and references therein). This variant is reported in ClinVar (Variation ID: 15189) and is observed in 1:400 live births in the Sardinian population (see HbVar database link and references therein). Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES HbVar link: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=239 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 25, 2023 | The HBB c.34G>A (p.Val12Ile) variant, also known as Hb Hamilton, is reported as having normal stability. Individuals who are heterozygous for this variant have a normal clinical presentation (PMID: 1428944 (1992), 19429541 (2009), 19727720 (2010)). Based on the available information, we are unable to determine the clinical significance of this variant. - |
beta Thalassemia Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2023 | Variant summary: HBB c.34G>A (p.Val12Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251232 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HBB causing Hemoglobinopathy (6e-05 vs 0.011), allowing no conclusion about variant significance. c.34G>A has been reported in the literature in individuals with moderate/mild anemia or no symptom and Autism (e.g. Manca_1987, Su_1992, Brunner-Agten_2010, Xinh_2022, Fu_2022, Zhou_2022). These reports do not provide unequivocal conclusions about association of the variant with Hemoglobinopathy. Co-occurrence with a pathogenic variant on the same allele has been reported in a child affected with sickle cell syndrome (HBB c.364G>A, p.Glu122Lys; Prehu_2002), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19727720, 35982160, 3623977, 11939508, 29319890, 1428944, 35023007, 35982159). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin 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 | May 03, 2022 | - - |
Fetal hemoglobin quantitative trait locus 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hemoglobin E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Hb SS disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
HEMOGLOBIN HAMILTON Other:1
other, no assertion criteria provided | literature only | OMIM | Dec 12, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at