rs121909824

Positions:

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

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_Very_Strong

The NM_000518.5(HBB):​c.380T>G​(p.Val127Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V127A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.0220

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 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 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 chr11-5225662-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 15201.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP5: Variant 11-5225662-A-C is Pathogenic according to our data. Variant chr11-5225662-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-5225662-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.380T>G	p.Val127Gly	missense_variant	3/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.380T>G	p.Val127Gly	missense_variant	3/3	1	NM_000518.5	P1
HBB	ENST00000647020.1	c.380T>G	p.Val127Gly	missense_variant	3/3			P1
HBB	ENST00000475226.1	n.312T>G		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*196T>G		3_prime_UTR_variant, NMD_transcript_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461774 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 15483). This variant is also known as Hb Dhonburi, Hb Neapolis and p.Val126Gly. This missense change has been observed in individual(s) with thalassemia intermedia (PMID: 1463768, 17007829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 127 of the HBB protein (p.Val127Gly). -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 28, 2019	The best available variant frequency is uninformative. Found in at least one symptomatic patient. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	The Hb Dhonburi (Neapolis) variant (HBB: c.380T>G p.Val127Gly, also known as Val126Gly when numbered from the mature protein, rs33925391, HbVar ID: 521) has been reported in the heterozygous state in individuals with mild microcytosis and hypochromia (see HbVar link, Divoky 1992, Khamphikham 2022, Moghimi 2004). This variant is reported in ClinVar (Variation ID: 15483). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Hb Dhonburi is electrophoretically silent, but is reported to be mildly unstable in non-physiologic conditions (Bardakdjian-Michau 1990, Pagano 1991). This variant has been associated with a mild beta thalassemia phenotype with variable clinical presentation when in combination with a beta(0) HBB variant on the opposite chromosome (Bardakdjian-Michau 1990). However, an individual from the same family who was compound heterozygous for Hb E/Hb Dhonburi had hematological findings that could be explained by Hb E alone. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.67). Based on available information, the Hb Dhonburi variant is likely to be a mildly unstable structural variant and is considered likely pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Bardakdjian-Michau J et al. Hemoglobin Dhonburi alpha 2 beta 2 126 (H4) Val----Gly: a new unstable beta variant producing a beta-thalassemia intermedia phenotype in association with beta zero-thalassemia. Am J Hematol. 1990 Oct;35(2):96-9. PMID: 2399911. Divoky V et al. Heterozygosity for the IVS-I-5 (G-->C) mutation with a G-->A change at codon 18 (Val-->Met; Hb Baden) in cis and a T-->G mutation at codon 126 (Val-->Gly; Hb Dhonburi) in trans resulting in a thalassemia intermedia. Biochim Biophys Acta. 1992 Dec 10;1180(2):173-9. PMID: 1463768. Khamphikham P et al. Strong Positive Dichlorophenolindophenol Precipitation Suggests Hb Dhonburi (or Hb Neapolis) (HBB: c.380T>G) Inheritance in a Couple at Risk for Severe ß-Thalassemia. Hemoglobin. 2022 May;46(3):184-186. PMID: 35543019. Moghimi B et al. Hb Dhonburi (Neapolis) [beta126(H4)Val-->Gly] identified in a family from northern Iran. Hemoglobin. 2004;28(4):353-6. PMID: 15658193. Pagano L et al. Hemoglobin Neapolis, beta 126(H4)Val----Gly: a novel beta-chain variant associated with a mild beta-thalassemia phenotype and displaying anomalous stability features. Blood. 1991 Dec 1;78(11):3070-5. PMID: 1954392. -

beta Thalassemia Pathogenic:2

Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2018	- -

Hemoglobinopathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2004

- -

Beta thalassemia intermedia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 01, 2021

Variant summary: HBB c.380T>G (p.Val127Gly; Hb Dhonburi or Hb Neapolis) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251316 control chromosomes (gnomAD). However, it was detected in several clinically silent carriers in Italy and certain parts of Asia (Pagano_1991, Pagano_2007, Moghimi_2004, Viprakasit_2007, He_2017, Mankhemthong_2019). c.380T>G has been reported in the literature in multiple compound heterozygous individuals affected with Beta Thalassemia Intermedia, who also carried another HBB disease variant (usually for beta0 or severe beta+ thalassemia) in trans (e.g. Bardakdjian-Michau_1990, Divoky_1992, Pagano_2007). Compound heterozygous individuals who carried the variant of interest with the HbE variant (c.79G>A/p.Glu27Lys) in trans, were either reported as clinically silent (Bardakdjian-Michau_1990), or affected only with a mild beta thalassemia intermedia (Viprakasit_2007). The variant was also reported in a patient, who carried the Hb Lepore-Boston variant and was affected with a mild thalassemia intermedia (Pagano_1997). These data indicate that the variant is very likely to be associated with disease. The variant protein was demonstrated to be unstable under certain in vitro conditions (Pagano_1991, Divoky_1992). Four other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.21	N
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.8	D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.014	D;.
Polyphen		0.74	P;P
Vest4		0.79
MutPred		0.49		Gain of disorder (P = 0.0101);Gain of disorder (P = 0.0101);
MVP		0.84
MPC		0.054
ClinPred		0.77	D
GERP RS		0.17
Varity_R		0.50
gMVP		0.95

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: rs33925391; hg19: chr11-5246892;