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rs33936254

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000518.5(HBB):c.68A>T(p.Glu23Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E23G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

HBB
NM_000518.5 missense

Scores

3
8
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 1.78
Variant links:
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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 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 chr11-5226954-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.68A>T p.Glu23Val missense_variant 1/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.68A>T p.Glu23Val missense_variant 1/31 NM_000518.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 09, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoJul 17, 2018- -
HEMOGLOBIN D (GRANADA) Other:1
other, no assertion criteria providedliterature onlyOMIMDec 12, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Pathogenic
0.37
D
BayesDel_noAF
Pathogenic
0.30
Cadd
Benign
18
Dann
Uncertain
0.99
DEOGEN2
Benign
0.037
T;T;.;T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.66
FATHMM_MKL
Benign
0.44
N
M_CAP
Uncertain
0.28
D
MetaRNN
Uncertain
0.74
D;D;D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Uncertain
2.5
M;M;.;.
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.48
T
PROVEAN
Uncertain
-3.1
D;.;.;D
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D;.;.;D
Sift4G
Benign
0.17
T;.;.;.
Polyphen
0.0
B;B;.;.
Vest4
0.82
MutPred
0.71
Loss of disorder (P = 0.0615);Loss of disorder (P = 0.0615);Loss of disorder (P = 0.0615);Loss of disorder (P = 0.0615);
MVP
0.88
MPC
0.046
ClinPred
0.72
D
GERP RS
2.8
Varity_R
0.62
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.16
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs33936254; hg19: chr11-5248184; API