11-5225606-A-G

Position:

• chr11-5225606-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.436T>C​(p.Tyr146His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y146C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.61

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 9 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 chr11-5225605-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 15322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 11-5225606-A-G is Pathogenic according to our data. Variant chr11-5225606-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15112.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.436T>C	p.Tyr146His	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.436T>C	p.Tyr146His	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.436T>C	p.Tyr146His	missense_variant	3/3			P1
HBB	ENST00000633227.1	c.*252T>C		3_prime_UTR_variant, NMD_transcript_variant	3/3	3
HBB	ENST00000475226.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Erythrocytosis, familial, 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1976

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 02, 2020

The Hb Bethesda (HBB: c.436T>C; p.Tyr146His, also known as Tyr145His when numbered from the mature protein, rs33949869), is reported in the literature in the heterozygous state in multiple individuals affected with erythrocytosis (see link to HbVar, Franklin 1986, McClure 2006, Tamura 2015, van Zwieten 2014). This variant is reported in ClinVar (Variation ID: 15112), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 146 is highly conserved, and functional analyses of the variant protein show increased oxygen affinity (see link to HbVar, Franklin 1986). Additionally, other amino acid substitutions at this codon (Hb Nancy, Hb Osler, Hb Rainier, Hb McKees Rocks) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar IDs: 571, 572, 573, 574), and several hemoglobin variants with high oxygen affinity leading to erythrocytosis are located at the carboxy-terminal end of the HBB gene (Wajcman 2004). Based on available information, the Hb Bethesda variant is considered to be pathogenic. References: Link to HbVar for Hb Bethesda: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=570 Franklin IM et al. Increasing haemoglobin oxygen affinity to prevent sickling: abnormal haemoglobin variants as models. Br J Haematol. 1986 Oct;64(2):319-29. McClure RF et al. The JAK2 V617F mutation is absent in patients with erythrocytosis due to high oxygen affinity hemoglobin variants. Hemoglobin. 2006;30(4):487-9. Tamura S et al. A Japanese Family with Congenital Erythrocytosis Caused by Haemoglobin Bethesda. Intern Med. 2015;54(18):2389-93. van Zwieten R et al. Hemoglobin analyses in the Netherlands reveal more than 80 different variants including six novel ones. Hemoglobin. 2014;38(1):1-7. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. -

HEMOGLOBIN BETHESDA 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	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.5	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0050	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.89	P;P
Vest4		0.82
MutPred		0.85		Gain of disorder (P = 0.022);Gain of disorder (P = 0.022);
MVP		0.88
MPC		0.11
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.52
gMVP		0.94

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

Other links and lift over

dbSNP: rs33949869; hg19: chr11-5246836;