Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2_SupportingPM5BP4
The NM_000518(HBB):c.20A>C(p.Glu7Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E7Q) has been classified as Uncertain significance.
Verdict is Uncertain_significance. Variant got 4 ACMG points.
GnomAD3 genomesCov.: 32 GnomAD4 exome AF: 6.86e-7AC: 1AN: 1458400Hom.: 0 AF XY: 0.00AC XY: 0AN XY: 725786
Submissions by phenotype
|Likely benign, criteria provided, single submitter||clinical testing||Women's Health and Genetics/Laboratory Corporation of America, LabCorp||May 08, 2023||Variant summary: HBB c.20A>C (p.Glu7Ala), also known as the Hb G Makassar variant, results in a non-conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251180 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. However, c.20A>C has been reported in the literature in several healthy homozygous and heterozygous individuals, who were exclusively of Thai and Indonesian descent and identified as having abnormal hemoglobin bands through HPLC analysis, but were found to have normal blood test results and no clinical abnormalities (e.g., Blackwell_1970, Viprakasit_2002, Thongnoppakhun_2009, Saechan_2010, Sangkitporn_2002). In a compound heterozygous individual where a pathogenic variant was identified in trans, the individual only displayed a Beta-thalassemia minor phenotype (e.g., Viprakasit_2002). At least one publication reports experimental evidence evaluating an impact on protein function, showing that c.20A>C represents a benign variant that rescued the disease phenotype in a humanized mouse sickle cell model (e.g., Newby_2021). The following publications have been ascertained in the context of this evaluation (PMID: 1363932, 5509617, 34079130, 20838957, 12188388, 19460936, 12403489). One ClinVar submitter (evaluation after 2014) has cited the variant as other (in reference to Blackwell_1970 in which the variant was identified in a healthy heterozygous individual). Based on the evidence outlined above, the variant was classified as likely benign. -|
HEMOGLOBIN G (MAKASSAR)
|other, no assertion criteria provided||literature only||OMIM||Dec 12, 2017||- -|
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