rs34398074

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000518.5(HBB):​c.398A>C​(p.Lys133Thr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K133?) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

HBB
NM_000518.5 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.59
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 Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 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 chr11-5225645-T-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HBBNM_000518.5 linkuse as main transcriptc.398A>C p.Lys133Thr missense_variant 3/3 ENST00000335295.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HBBENST00000335295.4 linkuse as main transcriptc.398A>C p.Lys133Thr missense_variant 3/31 NM_000518.5 P1
HBBENST00000647020.1 linkuse as main transcriptc.398A>C p.Lys133Thr missense_variant 3/3 P1
HBBENST00000633227.1 linkuse as main transcriptc.*214A>C 3_prime_UTR_variant, NMD_transcript_variant 3/33
HBBENST00000475226.1 linkuse as main transcript downstream_gene_variant 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.49
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;T
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.95
.;D
M_CAP
Pathogenic
0.72
D
MetaRNN
Pathogenic
0.94
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
4.6
H;H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.8
D;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
0.78
MutPred
0.78
Loss of methylation at K133 (P = 0.0014);Loss of methylation at K133 (P = 0.0014);
MVP
0.99
MPC
0.27
ClinPred
1.0
D
GERP RS
3.5
Varity_R
0.57
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs34398074; hg19: chr11-5246874; API