11-5225679-T-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000518.5(HBB):āc.363A>Cā(p.Lys121Asn) 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 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K121E) 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_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251288Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727224
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:2
Variant summary: The HBB c.363A>C (p.Lys121Asn) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 121384 control chromosomes in the ExAC database; however, it was found in 4/552 control chromsomes in the Indian population at a frequency of 0.00725. Although this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803), all 4 alleles were from two healthy individuals whom were homozygous for the variant of interest, suggesting that it is unlikely to be pathogenic. Although this variant was also found in two individuals who were compound heterozygous for this variant and another BTHAL-0 variant, the subjects had BTHAL MINOR, suggesting the variant is clinically silent (Pinkerton_1979 and Hirsch_1997). The variant has also been found in patients with alpha-thalassemia and iron deficiency, renal calculi, diabetes mellitues and hypertension; the variety of observed phenotypes suggests that the variant is not associated with hemoglobinopathy. Although this variant has been shown to significantly delay crystallization of hemolysate (Hirsch_1997), its functional role in hemoglobinopathy is not clear. OMIM classified this variant as pathogenic, however, this classification has not been updated since 1979 and could be questionable. Taken together, this variant is classified as VUS-possibly benign variant. -
The Hb Riyadh variant (HBB: c.363A>C; p.Lys121Asn, also known as Lys120Asn when numbered from the mature protein, rs34726542, HbVar ID: 506) has been reported in several healthy individuals (HbVar database and references therein), and in the ClinVar database (Variation ID: 15329). The variant protein exhibits normal stability and oxygen affinity, and had no deleterious impact in the presence of a beta-0 thalassemia variant (HbVar database and references therein). This variant is found in the general population with an overall allele frequency of 0.0004% (1/251288 alleles) in the Genome Aggregation Database. Based on the absence of clinical symptoms associated with the variant, Hb Riyadh is considered to be benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/hbvar.html -
This variant is also known as Hb Riyadh (PMID: 1052171 (1976)) and Hb Karatsu (PMID: 893141 (1977)). In the published literature, homozygous asymptomatic persons from India (PMID: 24099628 (2014)) and asymptomatic heterozygous persons from Mexican and Japanese families have been identified (PMID: 893129 (1977), 893141 (1977), and Hidaka and Iuchi (1986) Kawasaki Med J 12(3):149). It was originally described in a Saudi Arabian woman who was likely also to have alpha thalassemia (PMID: 1052171 (1976)). Not long after, this variant was described in a woman from India who also carried a beta-0-thalassemia mutation but only showed a simple beta-thalassemia trait and no clinical effects (PMID: 511584 (1979)). Functional studies show this variant has normal stability (PMID: 893129 (1977) and 893141 (1977)) and normal oxygen affinity (PMID: 893129 (1977)). -
not specified Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at