rs121909809

Variant names:

• chr11-5225662-A-T
• rs33925391
• NM_000518.5:c.380T>A

Your query was ambiguous. Multiple possible variants found:

• chr11-5225662-A-T
• chr11-5225662-A-C
• chr11-5225662-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_000518.5(HBB):​c.380T>A​(p.Val127Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V127A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 O:1
• Conservation: PhyloP100: 0.0220
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• dominant beta-thalassemia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• hemoglobin M disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen
• beta thalassemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• beta-thalassemia HBB/LCRB

  Inheritance: AR, SD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• sickle cell disease and related diseases

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• erythrocytosis, familial, 6

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Heinz body anemia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• sickle cell disease

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia intermedia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• beta-thalassemia major

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• delta-beta-thalassemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin C-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hemoglobin E-beta-thalassemia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary persistence of fetal hemoglobin-sickle cell disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-beta-thalassemia disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin c disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin d disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• sickle cell-hemoglobin E disease syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298932 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 37 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 chr11-5225662-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 15483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 11-5225662-A-T is Pathogenic according to our data. Variant chr11-5225662-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 15201.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.380T>A	p.Val127Glu	missense_variant	Exon 3 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.380T>A	p.Val127Glu	missense_variant	Exon 3 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:2

Oct 27, 2023

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000518.5(HBB):c.380T>A (p.Val127Glu) has been previously reported as Hb Hofu and has been observed in Indian population (Pande et al, Purohit et al, Warghade et al). It has been submitted to ClinVar with conflicting interpretations of pathogenicity : VUS/Likely Pathogenic. In combination with a beta 0 variant it has been reported with a thalssemia intermedia phenotype and has been observed in asymptomatic as well as symptomatic indviduals in trans with sickle cell trait (Arends T et al,Brittenham G et al, Purohit et al). The p.Val127Glu variant is novel (not in any individuals) in gnomAD. The p.Val127Glu variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between valine and glutamic acid. In silico tools predict a damaging effect while the residue is weakly conserved across species. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:2

Jun 18, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Hb Hofu variant (HBB: c.380T>A; p.Val127Glu, also known as Val126Glu when numbered from the mature protein, rs33925391, HbVar ID: 519) is reported in the literature in the heterozygous state in both individuals with mild anemia and asymptomatic individuals (Purohit 2014, HbVar database and references therein). This variant was also reported in an individual with thalassemia intermedia who also carried a beta-0 variant (Pande 1995), though it has been described in trans to Hb S in both symptomatic and asymptomatic individuals (Huisman 1997, Purohit 2014, HbVar database). Hematological measurements in carriers indicate that Hb Hofu is a mildly unstable variant (Huisman 1997, Purohit 2014, HbVar database). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 127 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.646). Based on available information, the clinical significance of this variant is uncertain at this time. REFERENCES Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Huisman TH et al. Combinations of beta chain abnormal hemoglobins with each other or with beta-thalassemia determinants with known mutations: influence on phenotype. Clin Chem. 1997 Oct;43(10):1850-6. PMID: 9342003 Pande PL et al. Beta-thalassemia intermedia in an Indian female with the Hb Hofu (beta 126(H4)Val-->Glu)-beta zero-thalassemia (codons 8/9 (+G)) combination. Hemoglobin. 1995 Sep;19(5):301-6. PMID: 8537236 Purohit P et al. Clinical and molecular characterization of Hb Hofu in eastern India. Int J Lab Hematol. 2014 Feb;36(1):71-6. PMID: 23889802 -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Jan 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMOGLOBIN HOFU Other:1

Dec 12, 2017

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.46	.;T
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.5	H;H
PhyloP100		0.022
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		0.41	B;B
Vest4		0.84
MutPred		0.52		Gain of disorder (P = 0.0018);Gain of disorder (P = 0.0018);
MVP		0.78
MPC		0.063
ClinPred		0.78	D
GERP RS		0.17
Varity_R		0.51
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs33925391; hg19: chr11-5246892;