rs33985544

chr11-5226701-T-Cchr11-5226701-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000518.5(HBB):c.191A>G(p.His64Arg) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H64N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 7.37

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 11 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 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 chr11-5226702-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-5226701-T-C is Pathogenic according to our data. Variant chr11-5226701-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15400.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}. Variant chr11-5226701-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.191A>G	p.His64Arg	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.191A>G	p.His64Arg	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 08, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2022	The Hb Zurich variant (HBB: c.191A>G; p.His64Arg, also known as His63Arg when numbered from the mature protein, rs33985544, HbVar ID: 358) has been observed in the heterozygous state in asymptomatic individuals or associated with mild reticulocytosis (see HbVar database and references therein). This variant has been associated with episodes of severe drug-induced hemolytic anemia in patients after administration of oxidative drugs particularly sulfonamides (see HbVar, Aguinaga 1998, Miranda 1994). This variant has been reported as mildly unstable with increased oxygen affinity (Aguinaga 1998). This variant is reported in ClinVar (Variation ID: 15400) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 64 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.983). Based on available information, this variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Aguinaga MP et al. Molecular diagnosis and characterization of Hb Zürich [beta63(E7)His-->Arg]] carriers in a Kentucky family. Hemoglobin. 1998 Sep-Nov;22(5-6):509-15. PMID: 9859934. Miranda SR et al. Identification of Hb Zürich [alpha 2 beta 2(63)(E7)His-->Arg] by DNA analysis in a Brazilian family. Hemoglobin. 1994 Sep;18(4-5):337-41. PMID: 7852089. -

Hemoglobinopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 22, 2024

Variant summary: HBB c.191A>G (p.His64Arg) results in a non-conservative amino acid change in the encoded protein sequence, altering a conserved residue (HGMD) in which another missense variant (p.His64Tyr) is classified as pathogenic. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251428 control chromosomes (gnomAD). c.191A>G has been reported in the literature in heterozygous individuals affected with hemolytic episodes, which was usually described as following sulfonamide treatment, as well as in healthy relatives (e.g. Huisman_1961, Frick_1962, Rieder_1965, Dickerman_1973, Murata_1982, Miranda_1994, Aguinaga_1998). It was also found in the compound heterozygous state with a pathogenic variant in an individual with a phenotype ressembling beta thalassemia intermedia (Yan_2019). These data indicate that the variant is likely associated with hemoglobinopathy in the heterozygous state which manifests as a drug-induced reaction, and may also be associated with disease in the compound heterozygous state with a beta thalassemia allele. Publications report experimental evidence evaluating an impact on protein function (Zinkham_1980, Aguinaga_1998), finding evidence of protein instability and increased carbon monoxide affinity. The following publications have been ascertained in the context of this evaluation (PMID: 6175783, 13716725, 14314237, 4749206, 13895148, 7852089, 9859934, 7384813, 30900795). ClinVar contains an entry for this variant (Variation ID: 15400). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hemoglobin Zurich Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.;T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.5	D;.;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.99
MutPred		0.94		Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);Gain of MoRF binding (P = 0.0167);
MVP		0.99
MPC		0.25
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.91
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: rs33985544; hg19: chr11-5247931;