chr11-5225662-A-T

Position:

• chr11-5225662-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. 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:2 U:2 O:1
• 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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5225662-A-C is described in Lovd as [Pathogenic].
• 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 id is 15201.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.380T>A	p.Val127Glu	missense_variant	3/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.380T>A	p.Val127Glu	missense_variant	3/3	1	NM_000518.5	ENSP00000333994	P1
HBB	ENST00000647020.1	c.380T>A	p.Val127Glu	missense_variant	3/3			ENSP00000494175	P1
HBB	ENST00000475226.1	n.312T>A		non_coding_transcript_exon_variant	2/2	2
HBB	ENST00000633227.1	c.*196T>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	3		ENSP00000488004

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

beta Thalassemia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Oct 27, 2023	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 07, 2022	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 -

HEMOGLOBIN HOFU Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

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
MutationTaster	Benign	1.0	N
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

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;