chr11-5226713-T-G

Position:

• chr11-5226713-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000518.5(HBB):​c.179A>C​(p.Lys60Thr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K60E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 2.85

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]

HBB (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226712-CTT-CA is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.179A>C	p.Lys60Thr	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.179A>C	p.Lys60Thr	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2023	The Hb J-Honolulu variant (HBB: c.179A>C; p.Lys60Thr, also known as Lys59Thr when numbered from the mature protein; rs35537181; HbVar ID: 348), also known as Hb J Kaohsiung, is a structural hemoglobin variant that has been reported in the heterozygous state in several asymptomatic individuals with normal hematological parameters (see HbVar, Blackwell 1972, Lou 2014). This variant has also been observed in an individual with mild microcytic anemia who also carried the pathogenic Hb E variant, though it is not known if Hb J-Honolulu contributed to this individual's hematological symptoms (Panyasai 2017). This variant is reported in ClinVar (Variation ID: 15222). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.729). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Link to HbVar Database: https://globin.bx.psu.edu/hbvar/menu.html Blackwell RQ et al. Fast haemoglobin variant found in Hawaiian-Chinese-Caucasian family in Hawaii and a Chinese subject in taiwan. Vox Sang. 1972;22(5):469-73. PMID: 5032420. Lou JW et al. Prevalence and molecular characterization of structural hemoglobin variants in the Dongguan region of Guangdong province, southern China. Hemoglobin. 2014;38(4):282-6. PMID: 24985555. Panyasai S et al. Co-inheritance of Hb J-Kaohsiung (B59(E3) AAG>ACG, Lys>Thr) and HbE (B26(B8) GAG>AAG, Glu>Lys) in a Thai Woman. Indian J Hematol Blood Transfus. 2017 Dec;33(4):619-620. PMID: 29075081. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 05, 2024	The HBB c.179A>C (p.Lys60Thr) variant has been reported in the published literature in heterozygous reportedly healthy individuals (PMIDs: 5553980 (1971), 5032420 (1972), 24985555 (2014), 31164695 (2019)). There is a report of a woman affected with mild anemia and microcytosis who was also found to carry Hb E (PMID: 29075081 (2017)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1972

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;T;.;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.88	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	3.6	H;H;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.2	D;.;.;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.021	D;.;.;.
Polyphen		0.99	D;D;.;.
Vest4		0.66
MutPred		0.67		Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);Loss of methylation at K60 (P = 0.0119);
MVP		0.98
MPC		0.23
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.87
gMVP		0.85

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: rs35537181; hg19: chr11-5247943;