chr11-5226613-G-T

Position:

• chr11-5226613-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.279C>A​(p.His93Gln) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H93D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.56

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226613-G-Y is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 11-5226613-G-T is Pathogenic according to our data. Variant chr11-5226613-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 811500.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.279C>A	p.His93Gln	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.279C>A	p.His93Gln	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: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2019

The Hb Saint Etienne/Hb Istanbul variant (HBB: [c.279C>A or c.279C>G]; p.His93Gln, also known as His92Gln when numbered from the mature protein, rs34083951), is described in individuals with varying degrees of anemia, as well as in a family presenting with deep vein thrombosis and a strong family history of hemolytic anemia (see link to HbVar and references therein, Aksoy 1972, Au 2009). This variant is also reported in ClinVar (Variation ID: 15208). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Functional characterization of the variant protein indicates reduced hemoglobin stability with increased dissociation into dimers and precipitation in hemolysate (see link to HbVar and references therein, Aksoy 1972), an effect that has also been observed with another variant at this codon (His93Tyr; Bird 1988, Stamatoyannopoulos 1976). Additionally, other variants at this codon (His93Asn, His93Pro) have been described in individuals and families with chronic anemia (Finney 1975, Wajcman 1991). Based on available information, the Hb Saint Etienne/Hb Istanbul variant is considered to be pathogenic. REFERENCES Link to HbVar for Hb Saint Etienne: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=432&.cgifields=histD Aksoy M et al. Hemoglobin Istanbul: substitution of glutamine for histidine in a proximal histidine (F8(92) ). J Clin Invest. 1972 Sep;51(9):2380-7. Au N et al. Two new examples of Hb St. Etienne [beta 92(F8)HisGln] in association with venous thrombosis. Hemoglobin. 2009;33(2):95-100. Bird A et al. Haemoglobin M-Hyde Park associated with polyagglutinable red blood cells in a South African family. Br J Haematol. 1988;68(4):459-64. Finney R et al. Hb Newcastle: beta92 (F8) His replaced by Pro. FEBS Lett. 1975 Dec 15;60(2):435-8. Stamatoyannopoulos G et al. Haemoglobin M Hyde Park occurring as a fresh mutation: diagnostic, structural, and genetic considerations. J Med Genet. 1976;13(2):142-7. Wajcman H et al. Hemoglobin Redondo [beta 92(F8) His----Asn]: an unstable hemoglobin variant associated with heme loss which occurs in two forms. Am J Hematol. 1991 Nov;38(3):194-200. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H;H;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.5	D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.96		Gain of ubiquitination at K96 (P = 0.0725);Gain of ubiquitination at K96 (P = 0.0725);Gain of ubiquitination at K96 (P = 0.0725);
MVP		0.92
MPC		0.24
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.92
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: rs34083951; hg19: chr11-5247843;