11-5225678-C-T

Position:

chr11-5225678-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM5PP3PP5_Very_Strong

The NM_000518.5(HBB):c.364G>A(p.Glu122Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E122A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:3

Conservation

PhyloP100: 4.94

Variant links:

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 links:

HBB (HGNC:):

HBB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5225678-C-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.775

PP5

Variant 11-5225678-C-T is Pathogenic according to our data. Variant chr11-5225678-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225678-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.364G>A	p.Glu122Lys	missense_variant	3/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.364G>A	p.Glu122Lys	missense_variant	3/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251306

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461810

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 17, 2024	The HBB c.364G>A (p.Glu122Lys) variant (also known as Hb O-Arab or p.Glu121Lys) has been described in individuals with normal clinical presentation when in heterozygosity and mild anemia when in homozygosity, and with structural hemoglobinopathy association (HbVar (http://globin.bx.psu.edu/) and ITHANET (http://www.ithanet.eu/)). It has also been identified in compound heterozygosity with the Hb S variant to cause severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those homozygous sickle cell anemia and higher severity relative to Hb SC disease, and described to cause increased red cell mean corpuscular hemoglobin concentration (MCHC) similar to that of Hb C (PMIDs: 20788973 (1960), 5481775 (1970), 10203101 (1999), 10583251 (1999), 22975760 (2013), 24880717 (2014), 32371413 (2020), 35064169 (2022), and 37554704 (2023)). Furthermore, when the variant is on the same chain as the Hb variant, these two changes are collectively known as HbS-Oman which can present from no to a dominant expression of a sickle cell anemia clinical syndrome (PMIDs: 9834244 (1998) and 10583251 (1999)). This variant has also been reported along with Hb D-Los Angeles or Hb C in individuals with hemoglobinopathies including a mild microcytic anemia (PMIDs: 31973650 (2020) and 33091040 (2020)). In vitro studies have shown that this variant results in the impaired hemoglobin function in Hb S compound heterozygous individuals (PMIDs: 5481775 (1970), 3859465 (1985), and 10583251 (1999)). The frequency of this variant in the general population, 0.000014 (4/282706 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2023	The Hb O-Arab variant (HBB: c.364G>A; p.Glu122Lys, also known as Glu121Lys when numbered from the mature protein, rs33946267, HbVar ID: 510) is not associated with clinical manifestations in heterozygous carriers but can cause sickling disease when found in trans to Hb S or Hb C (Milner 1970, Ramot 1960, Rossi 2011, Zimmerman 1999, HbVar database and references therein). This variant has also been reported in cis to Hb S in a doubly substituted variant known as Hb S-Oman (HbVar ID: 687, Langdown 1989, HbVar database and references therein) which causes red cell sickling and has been reported in heterozygous individuals either with sickle cell disease or that were asymptomatic, though individuals with less severe clinical symptoms often had alpha thalassemia trait (Al Balushi 2017, Nagel 1998). Functional characterization of the Hb O-Arab variant globin in the presence of Hb S indicates that the Hb S/Hb O-Arab hemoglobin precipitates at a lower concentration that Hb S/Hb S or HbS/Hb A, suggestive of a strong sickling effect (Milner 1970). Hb O-Arab is listed as pathogenic by multiple laboratories in ClinVar (Variation ID: 15292), and it is found in the general population with an overall allele frequency of 0.001% (4/282706 alleles) in the Genome Aggregation Database. Based on available information, the variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Al Balushi HWM et al. The super sickling haemoglobin HbS-Oman: a study of red cell sickling, K+ permeability and associations with disease severity in patients heterozygous for HbA and HbS-Oman (HbA/S-Oman genotype). Br J Haematol. 2017 Oct;179(2):256-265. PMID: 28699687. Langdown JV et al. A new doubly substituted sickling haemoglobin: HbS-Oman. Br J Haematol. 1989 Mar;71(3):443-4. PMID: 2930724. Milner P et al. Hemoglobin O arab in four negro families and its interaction with hemoglobin S and hemoglobin C. N Engl J Med. 1970; 283(26):1417-25. PMID: 5481775 Nagel RL et al. HbS-oman heterozygote: a new dominant sickle syndrome. Blood. 1998 Dec 1;92(11):4375-82. PMID: 9834244. Ramot B et al. Haemoglobin O in An Arab Family. Br Med J. 1960; 2(5208):1262-4. PMID: 20788973. Rossi P et al. Bone marrow necrosis and sickle cell crisis associated with double heterozygosity for HbS and HbOARAB. Am J Hematol. 2011; 86(3):309-10. PMID: 20954261. Zimmerman S et al. Hemoglobin S/O(Arab): thirteen new cases and review of the literature. Am J Hematol. 1999; 60(4):279-84. PMID: 10203101. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 122 of the HBB protein (p.Glu122Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with sickle cell anemia (PMID: 3859465, 5481775). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as HbO-Arab or p.Glu121Lys. ClinVar contains an entry for this variant (Variation ID: 15292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HBB protein function. This variant disrupts the p.Glu122 amino acid residue in HBB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24245819, 24616059, 25666204). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hb SS disease

Pathogenic:2Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	May 09, 2018	[ACMG/AMP: PS4, PM2, PM3, PP5] This alteration has a prevalence that is significantly increased compared with controls (RR/OR > 5; CI does not include 1.0) [PS4], is absent from or rarely observed in large-scale population databases [PM2], is detected in trans with a known pathogenic variant [PM3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5]. -

beta Thalassemia

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_000518.4(HBB):c.364G>A(E122K, aka Hb O-Arab) is classified as pathogenic in the context of Hb beta chain-related hemoglobinopathy and is associated with hemoglobin O-Arab. Sources cited for classification include the following: PMID 1112610, 893136 and 5481775. Classification of NM_000518.4(HBB):c.364G>A(E122K, aka Hb O-Arab) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 25, 2022

- -

Sickle cell-Hemoglobin O Arab disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 22, 2016

Variant summary: The HBB c.364G>A (p.Glu122Lys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121410 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). this missense variant, also called Hb O-Thrace or Egypt, is a well-known variant that associates with Hb O disease (sickle cell disease and beta-thalassemia). When variant is seen in homozygous state, it does not cause BTHAL, but instead a mild anemia. When seen in trans with Hb S, it causes severe SICKLE disease similar to Hb S homozyotes. When seen in trans with BTHAL DV, it causes a mild to moderately severe anemia (which can have similarities to BTHAL-intermedia) which is worse than the anemia seen in Hb O homozygotes. Studies (Milner_NEJM_1970 and Rachmilewitz_HumGenet_1985) have shown hemoglobin function was impaired in patients with compound het for Hb O-Arab and Hb S. In addition, multiple reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

HEMOGLOBIN EGYPT

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

HEMOGLOBIN O (ARAB)

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

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.063

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Uncertain

0.31

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Benign

0.41

PROVEAN

Uncertain

-2.5

N;.

REVEL

Uncertain

0.62

Sift

Uncertain

0.0040

D;.

Sift4G

Benign

0.13

T;.

Polyphen

0.75

P;P

Vest4

0.46

MutPred

0.66

Gain of methylation at E122 (P = 6e-04);Gain of methylation at E122 (P = 6e-04);

MVP

0.99

MPC

0.046

ClinPred

0.51

GERP RS

4.7

Varity_R

0.42

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over