11-5226702-G-T

Variant names:

• chr11-5226702-G-T
• rs33922873
• NM_000518.5:c.190C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000518.5(HBB):​c.190C>A​(p.His64Asn) variant causes a missense change involving the alteration of a 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H64R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.10

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226701-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-5226702-G-T is Pathogenic according to our data. Variant chr11-5226702-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 694445.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	c.190C>A	p.His64Asn	missense_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.190C>A	p.His64Asn	missense_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

HEMOGLOBIN HANA Pathogenic:1

Nov 14, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

METHEMOGLOBINEMIA, BETA TYPE Pathogenic:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.190C>A (p.His64Asn) variant in the HBB gene has been reported previously in a heterozygous state in individuals affected with Methaemoglobinaemia. In a study of 8-year-old girl of Senegalese origin, Sanger sequencing of the α- and β-globin genes revealed heterozygosity for a variant in the HBB gene (p.His64Asn) previously annotated as Hb Haná.7 Hb Haná exhibit amino acid substitutions within the haeme pocket, associated with strong dysfunctional effects, including destabilisation, increased rates of MetHb formation and haeme loss, leading to hemolytic anaemia (Le Calvez et al., 2023). Different amino acid change (p.His64Tyr, p.His64Arg) is reported as a known pathogenic variant (Göttgens et al., 2021). This variant has been reported to the ClinVar database as Pathogenic. This variant is reported is absent in the gnomAD Exomes. The amino acid His at position 64 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The amino acid change p.His64Asn in HBB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	.;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.6	D;.;.;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;.;D
Sift4G	Uncertain	0.0070	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.98
MutPred		0.96		Loss of methylation at K62 (P = 0.1415);Loss of methylation at K62 (P = 0.1415);Loss of methylation at K62 (P = 0.1415);Loss of methylation at K62 (P = 0.1415);
MVP		0.99
MPC		0.26
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.93
gMVP		0.98

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: rs33922873; hg19: chr11-5247932;