rs33922873

Positions:

• chr11-5226702-G-A
• chr11-5226702-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000518.5(HBB):​c.190C>T​(p.His64Tyr) 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: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• 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]

HBB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 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, 0.989
• PP5: Variant 11-5226702-G-A is Pathogenic according to our data. Variant chr11-5226702-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5226702-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.190C>T	p.His64Tyr	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.190C>T	p.His64Tyr	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2019	Variant summary: HBB c.190C>T (p.His64Tyr) results in a conservative amino acid change located in a heme binding site (InterPro) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251426 control chromosomes (gnomAD). The variant (also known as Hb M-Saskatoon) is widely regarded as causing hemoglobin M (HbM) disease, and has been reported in the literature in several affected individuals (e.g. Efremov_1974, Waye_1994, Suryantoro_1995, Kedar_2005, Brunner-Agten_2010, Garcia-Morin_2019). The disorder was observed to be inherited in an autosomal dominant pattern, often occurring as a de novo mutation. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2019

- -

HEMOGLOBIN M (RADOM) METHEMOGLOBINEMIA, BETA TYPE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1995

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 05, 2024

The HBB c.190C>T (p.His64Tyr) variant (also known as Hb M Saskatoon and H63Y) has been reported in the published literature in individuals/families affected with autosomal dominant methemoglobinemia (PMIDs: 34789072 (2021), 4841979 (1974), 13897827 (1961), 20324533 (1950)) and has been observed to occur de novo (PMIDs: 19727720 (2010), 15929117 (2005), 7713749 (1994)). Functional studies have reported that this variant shows increased oxygen affinity, increased auto-oxidation, and reduced stability (PMIDs: 15929117 (2005), 4086306 (1985), 7372598 (1980), 6248489 (1980), 4301455 (1968), 5851873 (1965)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is associated with autosomal dominant methemoglobinemia, however, we are unable to determine the clinical significance of this variant as it relates to the severity of beta thalassemia when a pathogenic variant occurs in trans. Testing affected family members could help clarify the clinical significance of this variant. Genetic counseling is recommended. -

HEMOGLOBIN M (SASKATOON) Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.7	D;.;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0030	D;.;.;D
Sift4G	Uncertain	0.0050	D;.;.;.
Polyphen		0.96	D;D;.;.
Vest4		0.98
MutPred		0.95		Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);
MVP		0.98
MPC		0.086
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.99

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;