chr11-5225606-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000518.5(HBB):c.436T>A(p.Tyr146Asn) variant causes a missense change. 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y146C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
HBB
NM_000518.5 missense
NM_000518.5 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 6.61
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 Pathogenic. Variant got 12 ACMG points.
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 uncertain in NM_000518.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-5225605-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 11-5225606-A-T is Pathogenic according to our data. Variant chr11-5225606-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 633256.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HBB | NM_000518.5 | c.436T>A | p.Tyr146Asn | missense_variant | 3/3 | ENST00000335295.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HBB | ENST00000335295.4 | c.436T>A | p.Tyr146Asn | missense_variant | 3/3 | 1 | NM_000518.5 | P1 | |
HBB | ENST00000647020.1 | c.436T>A | p.Tyr146Asn | missense_variant | 3/3 | P1 | |||
HBB | ENST00000633227.1 | c.*252T>A | 3_prime_UTR_variant, NMD_transcript_variant | 3/3 | 3 | ||||
HBB | ENST00000475226.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Erythrocytosis, familial, 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1997 | - - |
Hemoglobinopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2018 | Variant summary: HBB c.436T>A (p.Tyr146Asn, a.k.a. Hb Olser) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. These data indicate that the variant is likely to be associated with disease. The variant allele was absent in 121380 control chromosomes (in ExAC). The variant has been reported in several individuals affected with erythrocytosis (Hutt 1996, Charache 1975, Kattamis 1997). Experimental evidence demonstrated a highly increased oxygen affinity for the variant hemoglobin (Charache 1975, Kattamis 1997), that subsequently, can cause tissue hypoxia and secondary erythrocytosis. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Uncertain
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;D
Vest4
MutPred
Loss of ubiquitination at K145 (P = 0.0383);Loss of ubiquitination at K145 (P = 0.0383);
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