11-5225659-T-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):c.383A>C(p.Gln128Pro) variant causes a missense change involving the alteration of a 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q128E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.21

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 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 chr11-5225659-T-C is described in ClinVar as [Pathogenic, other]. Clinvar id is 15537.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 11-5225659-T-G is Pathogenic according to our data. Variant chr11-5225659-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 15409.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5225659-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.383A>C	p.Gln128Pro	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.383A>C	p.Gln128Pro	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.383A>C	p.Gln128Pro	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.315A>C		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*199A>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jun 07, 2019

The Hb Houston variant (HBB: c.383A>C; p.Gln128Pro, also known as Gln127Pro when numbered from the mature protein, rs33910569) is reported in the literature in at least one family affected with a dominant form of beta (+) thalassemia (Kazazian 1992, HbVar). Functional analyses show that the variant protein is highly unstable, and results in the degradation of hemoglobin tetramers, leading to the severe phenotype (Kazazian 1992). This variant is reported in ClinVar (Variation ID: 15409), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamine at codon 128 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other variants at this codon (Hb Dieppe, c.383A>G; p.Gln128Arg, Hb Brest, c.382C>A; Gln128Lys) have been reported in individuals with dominant beta (+) thalassemia (Girodon 1992, HbVar and references therein), and most dominant beta thalassemias are caused by variants in the same exon (Thein 1990). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar for Hb Houston: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=959&.cgifields=histD Girodon E et al. Rapid molecular characterization of mutations leading to unstable hemoglobin beta-chain variants. Ann Hematol. 1992 Oct;65(4):188-92. Kazazian HH Jr et al. Dominant thalassemia-like phenotypes associated with mutations in exon 3 of the beta-globin gene. Blood. 1992 Jun 1;79(11):3014-8. Thein S et al. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc Natl Acad Sci U S A. 1990 May;87(10):3924-8. -

Beta-Houston-thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1986

- -

Beta-plus-thalassemia, dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1986

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.76		Gain of glycosylation at Q128 (P = 0.0342);Gain of glycosylation at Q128 (P = 0.0342);
MVP		0.99
MPC		0.27
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.99

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: rs33910569; hg19: chr11-5246889;