chr11-5226629-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6
The NM_000518.5(HBB):c.263C>A(p.Thr88Lys) 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 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. T88I) has been classified as Benign.
Frequency
Consequence
NM_000518.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.263C>A | p.Thr88Lys | missense_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.263C>A | p.Thr88Lys | missense_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461864Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 20, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2021 | Variant summary: c.263C>A (p.Thr88Lys), also known as Hb D-Ibadan, 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 251424 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.263C>A has been reported in one Nigerian family, a propositus and his mother were compound heterozygous for this variant and HbS (DV) and both were clinically asymptomatic (Watson-Williams_1965). Similarly, in two other subjects of African-American ethnicity, compound heterozygosity with other DVs (HbS and c.-79A>G) did not cause disease (Redding-Lallinger_2002). Additionally, in one reported case who was compound heterozygosity with HbC had mild anemia (Kundrapu_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
beta Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 18, 2020 | - - |
HEMOGLOBIN D (IBADAN) 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