11-5226735-C-T

Variant names:

• chr11-5226735-C-T
• rs33961886
• NM_000518.5:c.157G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM1 BP6

The NM_000518.5(HBB):​c.157G>A​(p.Asp53Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D53G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.65
• Publications: 7 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 1 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 33 uncertain in NM_000518.5
• BP6: Variant 11-5226735-C-T is Benign according to our data. Variant chr11-5226735-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15302.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.157G>A	p.Asp53Asn	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.157G>A	p.Asp53Asn	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461876 Hom.: 0 Cov.: 36 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Aug 10, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Osu Christiansborg variant (HBB: c.157G>A; p.Asp53Asn, also known as Asp52Asn when numbered from the mature protein, rs33961886, HbVar ID: 334) has not been associated with any clinically significant phenotype even when found in trans with other hemoglobin variants (Hb C, Hb S) (see HbVar link, Boucher 2016, Cook 2013, Konotey-Ahulu 1971). This variant is reported in ClinVar (Variation ID: 15302) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartic acid at codon 53 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.4). Based on available information, the Hb Osu Christiansborg variant is considered to be benign. References: Link to HbVar Database: https://globin.bx.psu.edu/hbvar/hbvar.html Boucher MO et al. Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G>A) and Hb Osu Christiansborg (HBB: c.157G>A). Hemoglobin. 2016; 40(3):208-9. PMID: 27117572. Cook CM et al. The clinical and laboratory spectrum of Hb C (beta6(A3)Glu->Lys, GAG>AAG) disease. Hemoglobin. 2013; 37(1):16-25. PMID: 23297836. Konotey-Ahulu FI et al. Haemoglobin Osu-Christiansborg: a new beta-chain variant of haemoglobin A (beta52 (D3) aspartic acid leads to asparagine) in combination with haemoglobin S. J Med Genet. 1971; 8(3):302-5. PMID: 5097135. -

Aug 07, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HBB c.157G>A (p.Asp53Asn) variant (also known as Hb Osu Christiansborg) has been reported in the published literature as having normal stability (PMID: 640855 (1978)). Individuals heterozygous for this variant have a normal clinical presentation (HbVar (http://globin.cse.psu.edu/cgi-bin/hbvar/counter), PMIDs: 15008267 (2004), 640855 (1978)). Compound heterozygosity of this variant with Hb S did not presented with sickle cell disease (PMID: 5097135 (1971), and J Hematol (2016):5(1):74-75). Compound heterozygosity of this variant with Hb C has been reported in individuals with mild microcytic anemia (PMIDs: 27117572 (2016), 23297836 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152152 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified Benign:2

Mar 14, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HBB c.157G>A (p.Asp53Asn) also known as Haemoglobin Osu-Christiansborg results in a conservative amino acid change located in the Globin domain (IPR000971) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.157G>A has been reported in the literature and regognized by many reports as a non-pathological beta-gene mutant (example, Konotey-Ahulu_1971, Rodrigues Souza_2004, van Zwwieten_2014). It migrates identically to HbS on haemoglobin electrophoresis. It was observed in apparently unaffected individuals in the heterozygous state or in compound heterozygosity with HbS or HbC with normal hematological findings and hemoglobin pattern suitable to their carrier status, respectively. Based on Kapoor et al (2005), this variant may cause a falsely elevated level of HbA1c. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=3; likely benign, n=1, VUS, n=1). Based on the lack of conclusive evidence reporting this variant homozygously or in trans with other b+-thal or b0-thal variants as evidence outlined above, the variant was classified as likely benign for Hemoglobinopathy. -

Dec 12, 2017

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

beta Thalassemia Benign:2

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2017

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	6.9
DANN	Benign	0.96
DEOGEN2	Benign	0.037	T;T;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.63	.;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.8	L;L;.;.
PhyloP100		-1.6
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.42	N;.;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.061	T;.;.;D
Sift4G	Benign	0.41	T;.;.;.
Polyphen		0.0	B;B;.;.
Vest4		0.50
MutPred		0.53		Loss of phosphorylation at T51 (P = 0.1227);Loss of phosphorylation at T51 (P = 0.1227);Loss of phosphorylation at T51 (P = 0.1227);Loss of phosphorylation at T51 (P = 0.1227);
MVP		0.87
MPC		0.034
ClinPred		0.99	D
GERP RS		-4.8
PromoterAI		-0.011	Neutral
Varity_R		0.21
gMVP		0.38
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs33961886; hg19: chr11-5247965;