dbSNP rs33993568: HBB:p.Thr88Ile (chr11-5226629-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_000518.5(HBB):c.263C>T(p.Thr88Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1B:1

Conservation

PhyloP100: 0.799

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;

PP5

Variant 11-5226629-G-A is Pathogenic according to our data. Variant chr11-5226629-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15493.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.263C>T	p.Thr88Ile	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.263C>T	p.Thr88Ile	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251424

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000445

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Aug 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Quebec-Chori variant (HBB: c.263C>T; p.Thr88Ile, also known as Thr87Ile when numbered from the mature protein, rs33993568, HbVar ID: 418) is not associated with clinical manifestations in heterozygous carriers but has been reported in trans to Hb S in multiple individuals with sickle cell disease (Goode 2020, Segal 2005, Tubman 2007, Witkowska 1991, HbVar database and references therein). The p.Thr88Ile variant is found in the non-Finnish European population with an allele frequency of 0.004% (4/113,718 alleles) in the Genome Aggregation Database (v2.1.1). Functional analyses suggest Hb Quebec-Chori exhibits normal oxygenation in isolation; however, the combination of Hb Quebec-Chori and Hb S is associated with increased sickling in hypoxic conditions compared to heterozygous Hb S alone (Witkowska 1991). Based on available information, the Hb Quebec-Chori variant is considered to be likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Goode E et al. Hemoglobin S/Hemoglobin Quebec-Chori Presenting as Sickle Cell Disease: A Case Report. J Pediatr Hematol Oncol. 2020 Nov;42(8):e775-e777. PMID: 32657857. Segal L and Discepola M. Idiopathic intracranial hypertension and sickle cell disease: two case reports. Can J Ophthalmol. 2005 Dec;40(6):764-7. PMID: 16391644. Tubman VN et al. Sickle cell disease caused by Hb S/Quebec-CHORI: treatment with hydroxyurea and response. Pediatr Blood Cancer. 2007 Aug;49(2):207-10. PMID: 17551985. Witkowska HE et al. Sickle cell disease in a patient with sickle cell trait and compound heterozygosity for hemoglobin S and hemoglobin Quebec-Chori. N Engl J Med. 1991 Oct 17;325(16):1150-4. PMID: 1891024. -

not specified

Benign:1

Dec 12, 2017

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

9.0

DANN

Benign

0.96

DEOGEN2

Benign

0.033

T;T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.81

.;T;T;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.44

T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

1.7

L;L;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;.;.;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.0080

D;.;.;D

Sift4G

Uncertain

0.046

D;.;.;.

Polyphen

0.020

B;B;.;.

Vest4

0.85

MVP

0.67

MPC

0.051

ClinPred

0.12

GERP RS

-7.3

Varity_R

0.15

gMVP

0.56

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

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