rs33919924

Positions:

• chr11-5226734-T-A
• chr11-5226734-T-C
• chr11-5226734-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000518.5(HBB):​c.158A>T​(p.Asp53Val) 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. D53A) 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: 0.0520

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226735-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.158A>T	p.Asp53Val	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.158A>T	p.Asp53Val	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

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 28, 2018

The Hb Akron c.158A>T; Asp52Val variant (rs33919924) has been described in the heterozygous state in an individual with normal clinical presentation in the HbVar database (see link). However, its phenotype when found with other globin variants is unknown. This variant is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, one other variant at this codon (c.157G>A, Asp52Asn) has been reported in trans with other hemoglobin variants (Hb C, Hb S) without any clinically significant phenotype (HbVar, Boucher 2016, Cook 2013, Konotey-Ahulu 1971), and is considered benign. The aspartic acid at codon 52 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the Asp52Val variant is uncertain at this time. References: Link to HbVar Database: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=338&.cgifields=histD Boucher MO et al Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G?>?A) and Hb Osu Christiansborg (HBB: c.157G?>?A). Hemoglobin. 2016 40(3):208-9. Cook CM et al. The clinical and laboratory spectrum of Hb C (Beta6(A3)Glu>Lys, GAG>AAG) disease. Hemoglobin. 2013 37(1):16-25. Konotey-Ahulu FI et al. Haemoglobin Osu-Christiansborg: a new beta-chain variant of haemoglobin A ( beta52 (D3) aspartic acid leads to asparagine) in combination with haemoglobin S. J Med Genet. 1971 8(3):302-5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.064	T;T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.59	.;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.49	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.2	M;M;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.2	N;.;.;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.018	D;.;.;D
Sift4G	Benign	0.21	T;.;.;.
Polyphen		0.017	B;B;.;.
Vest4		0.53
MutPred		0.41		Loss of disorder (P = 0.0322);Loss of disorder (P = 0.0322);Loss of disorder (P = 0.0322);Loss of disorder (P = 0.0322);
MVP		0.74
MPC		0.044
ClinPred		0.32	T
GERP RS		-10
Varity_R		0.36
gMVP		0.59

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: rs33919924; hg19: chr11-5247964;