Variant rs33987903 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000518.5(HBB):c.248A>T(p.Lys83Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

HBB
NM_000518.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 3.80

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 11-5226644-T-A is Pathogenic according to our data. Variant chr11-5226644-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 15193.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5 link	c.248A>T	p.Lys83Met	missense_variant	2/3	ENST00000335295.4	NP_000509.1	P68871D9YZU5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4 link	c.248A>T	p.Lys83Met	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3		P68871

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251438

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135890

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:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727244

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:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Erythrocytosis, familial, 6

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1976

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 12, 2021

The Hb Helsinki variant (HBB: c.248A>T; p.Lys83Met, also known as Lys82Met when numbered from the mature protein, rs33987903) has been reported in the heterozygous state in multiple individuals with familial erythrocytosis (see HbVar and references therein). This variant has been observed to segregate with erythrocytosis in a family in a pattern consistent with autosomal dominant inheritance (Ikkala 1976). Additionally, this variant was found to ameliorate clinical symptoms in an individual with HbH disease (Lee 2017). Functional analyses of the variant protein show increased oxygen affinity, and decreased binding of 2,3-DPG (Ikkala 1976). This variant is reported in ClinVar (Variation ID: 15193). Additionally, another variant at this codon Hb Rahere (c.248A>C, p.Lys83Thr) has been reported in individuals with mild erythrocytosis and is considered pathogenic (Lorkin 1975, Sugihara 1985). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The lysine at codon 83 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.946). Based on available information, the Hb Helsinki variant is considered to be pathogenic. References: Link to HbVar for Hb Helsinki: https://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=407&.cgifields=histD Ikkala E et al. Hb Helsinki: a variant with a high oxygen affinity and a substitution at a 2,3-DPG binding site (beta82(EF60 Lys replaced by Met). Acta Haematol. 1976;56(5):257-75. Lee SY et al. Coinheritance of High Oxygen Affinity Hb Helsinki (HBB: c.248A>T; ß82(EF6)Lys-Met) with Hb H Disease. Hemoglobin. 2017 May;41(3):209-212. Lorkin PA et al. Haemoglobin Rahere (beta Lys-Thr): A new high affinity haemoglobin associated with decreased 2, 3-diphosphoglycerate binding and relative polycythaemia. Br Med J. 1975 Oct 25;4(5990):200-2. Sugihara J et al. Hemoglobin Rahere, a human hemoglobin variant with amino acid substitution at the 2,3-diphosphoglycerate binding site. Functional consequences of the alteration and effects of bezafibrate on the oxygen bindings. J Clin Invest. 1985 Sep;76(3):1169-73. -

HEMOGLOBIN HELSINKI

Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.054

T;T;.;T

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

H;H;.;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.6

D;.;.;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;.;.;D

Sift4G

Uncertain

0.0070

D;.;.;.

Polyphen

1.0

D;D;.;.

Vest4

0.87

MutPred

0.91

Loss of ubiquitination at K83 (P = 0.0255);Loss of ubiquitination at K83 (P = 0.0255);Loss of ubiquitination at K83 (P = 0.0255);Loss of ubiquitination at K83 (P = 0.0255);

MVP

0.99

MPC

0.21

ClinPred

0.99

GERP RS

5.1

Varity_R

0.74

gMVP

0.82

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