chr11-5226762-C-T

Position:

• chr11-5226762-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000518.5(HBB):​c.130G>A​(p.Glu44Lys) 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 benign 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. E44Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.219

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3232529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.130G>A	p.Glu44Lys	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.130G>A	p.Glu44Lys	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: 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 11, 2024

The HBB c.130G>A (p.Glu44Lys) variant has been reported in the published literature in an individual with thrombocytopenia (PMID: 29382003 (2017)). Additionally, the variant was reported in an individual who was compound heterozygous for the variant and was described to have showed microcytic and hypochromic RBC indices with a normal Hb level (PMID: 29313432 (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 conflicting predictions that this variant is deleterious or benign. 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
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;T;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.21	.;T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	2.0	M;M;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;.;.;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0050	D;.;.;D
Sift4G	Benign	0.40	T;.;.;.
Polyphen		0.0040	B;B;.;.
Vest4		0.58
MutPred		0.45		Gain of methylation at E44 (P = 6e-04);Gain of methylation at E44 (P = 6e-04);Gain of methylation at E44 (P = 6e-04);Gain of methylation at E44 (P = 6e-04);
MVP		0.90
MPC		0.045
ClinPred		0.21	T
GERP RS		4.2
Varity_R		0.47
gMVP		0.82

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: rs33922842; hg19: chr11-5247992; COSMIC: COSV58942837; COSMIC: COSV58942837;