rs33991472
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_000518.5(HBB):c.176C>G(p.Pro59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
HBB
NM_000518.5 missense
NM_000518.5 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 2.10
Genes affected
HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000518.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.917
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.176C>G | p.Pro59Arg | missense_variant | 2/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.176C>G | p.Pro59Arg | missense_variant | 2/3 | 1 | NM_000518.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0AN XY: 727244
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1461878
Hom.:
Cov.:
36
AF XY:
AC XY:
0
AN XY:
727244
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hemoglobinopathy Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 10, 1968 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 03, 2022 | Variant summary: HBB c.176C>G (p.Pro59Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251436 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.176C>G has been reported in the literature mainly as part of a complex allele known as Hb Dhofar, which includes the pathogenic variant c.90C>T ( (p.Gly30=) in cis. Hb Dhofar is common in the Sultanate of Oman where it has been reported in multiple compound heterozygous and homozygous individuals affected with Beta Thalassemia (e.g. Daar_2008). The variant c.176C>G in isolation (initially designated as Hb Yukuhashi), has been reported in at least one heterozygous individual in Japan (e.g. Fujita_1972, Darr_2008) and was determined to not differ significantly from hemoglobin A in oxygen affinity, heme-heme interaction, or the Bohr effect. These reports do not provide unequivocal conclusions about association of c.176C>G with Hemoglobinopathy. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, c.176C>G in isolation was classified as uncertain significance until additional evidence of clinical and/or functional importance become available. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Benign
T;T;.;T
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.;.
MutationTaster
Benign
N
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;D
Sift4G
Uncertain
D;.;.;.
Polyphen
D;D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0038);Gain of MoRF binding (P = 0.0038);Gain of MoRF binding (P = 0.0038);Gain of MoRF binding (P = 0.0038);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at