11-5226735-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM5

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. 12/21 in silico tools predict a benign 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. D53A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -1.65

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226735-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.157G>A	p.Asp53Asn	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.157G>A	p.Asp53Asn	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

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:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

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. -

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. -

not specified

Benign:2

Dec 12, 2017

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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. -

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

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

LIST_S2

Benign

0.63

.;T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.8

L;L;.;.

PrimateAI

Benign

0.35

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

GERP RS

-4.8

Varity_R

0.21

gMVP

0.38

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

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