11-5226955-C-T

Position:

chr11-5226955-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_000518.5(HBB):c.67G>A(p.Glu23Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E23A) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: 2.21

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000518.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-5226954-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461552

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74508

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:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 06, 2022

The Hb E-Saskatoon variant (HBB: c.67G>A, p.Glu23Lys, also known as Glu22Lys when numbered from the mature protein, rs33959855, HbVar ID: 264) has been reported in a heterozygous state in individuals with no clinical symptoms (HbVar database and reference therein), and comprises half of the total hemoglobin (Birben 2001). Individuals carrying the variant in-trans to Hb S or a beta thalassemia pathogenic variant exhibit mild-moderate hematological abnormalities (Birben 2001, Couto 2014, Theodoridou 2003, HbVar database and references therein), while a homozygous individual presented only mild anemia (Birben 2001). The variant is listed in ClinVar (Variation ID: 15162), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The at codon 23 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.536). Although Hb E-Saskatoon has not been associated with severe hematological symptoms, it has been associated with mild hematological changes in combination with other variants; overall, its clinical significance cannot be determined with certainty. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Birben E et al. Homozygosity for Hb E-Saskatoon (beta22(B4)Glu-->Lys) in a Turkish patient. Hemoglobin. 2001; 25(4):409-15. PMID: 11791874. Couto GK et al. Association of hemoglobin E-Saskatoon with hemoglobin S: report of the first case found in Brazil. Acta Haematol. 2014;131(2):84-7. PMID: 24081202. Theodoridou S et al. The first case of a compound heterozygosity for Hb E-Saskatoon and HbS. Haematologica. 2003 Mar;88(3):ECR08. PMID: 12651286. -

HEMOGLOBIN E (SASKATOON)

Other:1

other, no assertion criteria provided

literature only

OMIM

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;T;.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.35

.;T;T;T

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.3

M;M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.0

N;.;.;N

REVEL

Uncertain

0.54

Sift

Benign

0.031

D;.;.;D

Sift4G

Benign

0.22

T;.;.;.

Polyphen

0.0

B;B;.;.

Vest4

0.85

MutPred

0.76

Gain of ubiquitination at E23 (P = 0.0267);Gain of ubiquitination at E23 (P = 0.0267);Gain of ubiquitination at E23 (P = 0.0267);Gain of ubiquitination at E23 (P = 0.0267);

MVP

0.87

MPC

0.049

ClinPred

0.29

GERP RS

-0.27

Varity_R

0.22

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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