rs33912272
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate
The NM_000518.5(HBB):c.16C>T(p.Pro6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,610,008 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6R) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.16C>T | p.Pro6Ser | missense_variant | 1/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.16C>T | p.Pro6Ser | missense_variant | 1/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251132Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135712
GnomAD4 exome AF: 0.0000165 AC: 24AN: 1457718Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 12AN XY: 725420
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152290Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 02, 2021 | The Hb Tyne variant (HBB: c.16C>T; p.Pro6Ser, also known as Pro5Ser when numbered from the mature protein; rs33912272) has been described in the heterozygous state in individuals with normal hematological findings (Pullon 2017, HbVar database and references therein). However, the variant has also been observed in an individual with a clinical diagnosis of beta thalassemia who also carried HbS (Keser 2010). The proline at codon 5 is weakly conserved, and computational programs (PolyPhen-2, SIFT) predict that this variant is tolerated, although isopropanol stability tests indicate this variant is slightly unstable (Pullon 2017, HbVar database). Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. References: Link to HbVar database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=225 Keser I et al. Abnormal hemoglobins associated with the beta-globin gene in Antalya province, Turkey. Turk J Med Sci. 2010;40(1): 127-131. Pullon BM and Brennan SO. Two familial cases of Hb Tyne confirm instability as cause of low expression. Thalassemia Reports. 2017; 7(1). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 17, 2022 | Variant summary: HBB c.16C>T (p.Pro6Ser) 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 allele was found at a frequency of 4e-06 in 251132 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.16C>T has been reported in the literature in at least one compound heterozygous individual affected with Hemoglobinopathy (Kayisli_2005). The variant was also reported in a severely anemic patient with a truncating variant in cis and a pathogenic splice variant in trans (Agarwal_1997). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
beta Thalassemia Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 27, 2021 | - - |
HEMOGLOBIN TYNE 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