11-5226598-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000518.5(HBB):c.294C>G(p.His98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H98?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.0230

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 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 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 chr11-5226598-G-Y is described in ClinVar as [Pathogenic, other]. Clinvar id is 15259.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 11-5226598-G-C is Pathogenic according to our data. Variant chr11-5226598-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 801186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226598-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.294C>G	p.His98Gln	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.294C>G	p.His98Gln	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 31, 2019	Not found in the total gnomAD dataset, and the data are high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Moderate co-segregation with disease. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 03, 2020	The HBB c.294C>G; p.His98Gln variant (rs34515413), also known as Hb Malmo, is reported in the literature in multiple individuals affected with erythrocytosis (Santbergen 2014, HbVar and references therein). Additionally, other variants at this codon (c.294C>A; p.His98Gln, Hb Malmo and c.293A>T; p.His98Leu, Hb Wood) have been reported in individuals with erythrocytosis and are considered pathogenic (HbVar and references therein). The c.294C>G; p.His98Gln variant is reported in ClinVar (Variation ID: 15259), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The histidine at codon 98 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL 0.872). Based on available information, the Hb Malmo variant is considered to be pathogenic. References: Link to HbVar for Hb Malmo: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=444&.cgifields=histD Link to HbVar for Hb Wood: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=445&.cgifields=histD Santbergen B et al. At high altitude in the Netherlands: secondary erythrocytosis due to HB-Malmo. BMJ Case Rep. 2014 Mar 5;2014. pii: bcr2014203701. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T;.
Eigen	Benign	0.0073
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	M;M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.3	D;.;.
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.040	D;.;.
Polyphen		0.99	D;D;.
Vest4		0.96
MutPred		0.89		Gain of ubiquitination at K96 (P = 0.0671);Gain of ubiquitination at K96 (P = 0.0671);Gain of ubiquitination at K96 (P = 0.0671);
MVP		0.96
MPC		0.21
ClinPred		0.99	D
GERP RS		0.15
Varity_R		0.75
gMVP		0.79

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: rs34515413; hg19: chr11-5247828;