rs33924775

chr11-5226615-G-Achr11-5226615-G-Cchr11-5226615-G-T

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.277C>T(p.His93Tyr) 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. H93?) 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 O:3
• Conservation: PhyloP100: 7.51

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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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 chr11-5226613-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2664746.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 11-5226615-G-A is Pathogenic according to our data. Variant chr11-5226615-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 15255.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.277C>T	p.His93Tyr	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.277C>T	p.His93Tyr	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

Submissions summary: Pathogenic:2 Other:3

Revision: criteria provided, single submitter

Submissions by phenotype

Methemoglobinemia, beta-globin type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1998

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 14, 2023

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in de novo heterozygous individuals (PMIDs: 1398295 (1992), 32747614 (2020)) and in families that have been described as generally asymptomatic, but also affected with cyanosis, methemoglobinemia, and hemolytic anemia especially during crises (PMIDs: 5669922 (1968), 933112 (1976), 31267164 (2019), 33251782 (2020)). Functional studies have shown that this variant is unstable (PMID: 933112 (1976)). Based on the available information, this variant is classified as pathogenic. -

HEMOGLOBIN M (HYDE PARK) Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN M (AKITA) Other:1

other, no assertion criteria provided

literature only

OMIM

May 10, 2018

- -

HEMOGLOBIN M (MILWAUKEE 2) 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	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.7	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.7	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.95		Loss of methylation at K96 (P = 0.0553);Loss of methylation at K96 (P = 0.0553);Loss of methylation at K96 (P = 0.0553);
MVP		0.88
MPC		0.27
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.92
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: rs33924775; hg19: chr11-5247845;