11-5226660-G-C

Variant names:

• chr11-5226660-G-C
• rs33991294
• NM_000518.5:c.232C>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP3_Moderate BP6

The NM_000518.5(HBB):​c.232C>G​(p.His78Asp) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H78R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 0.993
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 37 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• BP6: Variant 11-5226660-G-C is Benign according to our data. Variant chr11-5226660-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15221.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.232C>G	p.His78Asp	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.232C>G	p.His78Asp	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Sep 14, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 13, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb J-Iran variant (HBB: c.232C>G; p.His78Asp, also known as His77Asp when numbered from the mature protein, rs33991294, HbVar ID: 393) is reported in the literature in multiple heterozygous individuals with no significant clinical or hematological abnormalities (Dehghani 2011, Delanoe-Garin 1986, Kurtoglu 2017, Rahbar 1967, Solouki 2023, HbVar database and references therein). One individual with microcytic anemia was reported to be apparently homozygous for Hb J-Iran, but the presence of a large deletion was not ruled out (Solouki 2023). Thr Hb J-Iran variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Functional studies suggest the variant is stable and has normal functional properties (Delanoe-Garin 1986), although its presence may interfere with measurement of hemoglobin A1c levels (Kurtoglu 2017). Based on available information, this variant is considered to be likely benign. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Dehghani SJ et al. Combined alpha-thalassemia and Hemoglobin J-Iran (Beta77 His ? Asp). A Family Study in southern Iran. Iran Red Crescent Med J. 2011 Aug;13(8):586-9. PMID: 22737531. Delanoe-Garin J et al. Hemoglobin J Iran alpha 2 beta 2 77 (EF1) his----Asp in a Russian-Armenian family. Hemoglobin. 1986;10(4):365-78. PMID: 2943700. Kurtoglu AU et al. Hemoglobin J-Iran (HBB c.232C>G): Interference with the assay of HbA1c. Clin Chim Acta. 2017 Feb;465:80-81. PMID: 28007613. Rahbar S et al. Abnormal haemoglobins in Iran. Observation of a new variant--haemoglobin J Iran (alpha-2-beta-2 77 His--Asp). Br Med J. 1967 Mar 18;1(5541):674-7. PMID: 6019668. Solouki A et al. Reporting two hemoglobin J Iran cases, molecular follow-up, or is it insignificant? Caspian J Intern Med. 2023 Summer;14(3):586-589. PMID: 37520881. -

HEMOGLOBIN J (IRAN) Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.060	T;T;.;T
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.59	.;T;T;T
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	M;M;.;.
PhyloP100		0.99
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.0	D;.;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.018	D;.;.;D
Sift4G	Uncertain	0.021	D;.;.;.
Polyphen		0.78	P;P;.;.
Vest4		0.87
MutPred		0.76		Gain of ubiquitination at K83 (P = 0.07);Gain of ubiquitination at K83 (P = 0.07);Gain of ubiquitination at K83 (P = 0.07);Gain of ubiquitination at K83 (P = 0.07);
MVP		0.94
MPC		0.14
ClinPred		0.83	D
GERP RS		1.9
PromoterAI		-0.024	Neutral
Varity_R		0.57
gMVP		0.75
Mutation Taster		=23/77	disease causing

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

Other links and lift over

dbSNP: rs33991294; hg19: chr11-5247890;