rs33964352

chr11-5225609-T-Achr11-5225609-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_000518.5(HBB):c.433A>T(p.Lys145Ter) variant causes a stop gained 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 (★). Synonymous variant affecting the same amino acid position (i.e. K145K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.433A>T	p.Lys145Ter	stop_gained	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.433A>T	p.Lys145Ter	stop_gained	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.433A>T	p.Lys145Ter	stop_gained	3/3			P1
HBB	ENST00000633227.1	c.*249A>T		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Apr 09, 2023

The HBB c.433A>T (p.Lys145*) nonsense variant is predicted to cause the premature termination of HBB protein synthesis resulting in deletion of the last three amino acids of the beta-globin chain. This variant has been associated with increased oxygen affinity, normal heat stability, and mild erythrocytosis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is described as heterozygous (Hb Cambridge-MA) and compound heterozygous with another Hb variant (Hb Kochi) in individuals with mild polycythemia whose hemoglobin showed increased oxygen affinity (PMIDs: 15768550 (2005) and 21077764 (2010)). Based on the available information, we are unable to determine the clinical significance of this variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	40
Dann	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D
Vest4		0.62
GERP RS		3.5

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

Other links and lift over

dbSNP: rs33964352; hg19: chr11-5246839;