11-5225611-T-C

Position:

• chr11-5225611-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000518.5(HBB):​c.431A>G​(p.His144Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H144D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 0.519

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5225611-T-C is Pathogenic according to our data. Variant chr11-5225611-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.431A>G	p.His144Arg	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.431A>G	p.His144Arg	missense_variant	3/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251362 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 23, 2020	The Hb Abruzzo variant (HBB: c.431A>G; p.His144Arg, also known as His143Arg when numbered from the mature protein; rs33918338) is reported in the literature in both the homozygous and heterozygous states in multiple individuals affected with erythrocytosis (Mosca 1993, Shrikhande 2016, Venkateswaran 2005, HbVar and references therein). This variant has been observed to segregate with erythrocytosis in at least one family (Venkateswaran 2005), and its occurrence in heterozygous affected individuals suggests it acts in a dominant manner (Mosca 1993, Shrikhande 2016, Venkateswaran 2005, HbVar and references therein). This variant is found only on a single chromosome (1/251362 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. The histidine at codon 144 is highly conserved, occurs in the functionally important 2,3-diphosphoglycerate binding site (Wajcman 2005), and functional studies indicate this variant exhibits increased oxygen affinity (Bonaventura 1975, Venkateswaran 2005). Additionally, other amino acid substitutions at this codon (p.His144Gln, p.His144Pro) exhibit increased oxygen affinity and are associated with erythrocytosis (Camps 2016, Jensen 1975, Wajcman 2005). Based on available information, the Hb Abruzzo variant is considered to be pathogenic. References: HbVar link for Hb Abruzzo: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=562 Bonaventura C et al. Hemoglobin Abruzzo (beta143 (H21) His replaced by Arg). Consequences of altering the 2,3-diphosphoglycerate binding site. J Biol Chem. 1975 Aug 25;250(16):6273-7. Camps C et al. Gene panel sequencing improves the diagnostic work-up of patients with idiopathic erythrocytosis and identifies new mutations. Haematologica. 2016 Nov;101(11):1306-1318. Jensen M et al. Hemoglobin Syracuse (alpha2beta2-143(H21)His leads to Pro), a new high-affinity variant detected by special electrophoretic methods. Observations on the auto-oxidation of normal and variant hemoglobins. J Clin Invest. 1975 Mar;55(3):469-77. Mosca A et al. Hb Abruzzo [beta 143(H21)His-->Arg] identified by mass spectrometry and DNA analysis. Hemoglobin. 1993 Jun;17(3):261-8. Shrikhande AV and Pawar PS. Association of a high oxygen affinity hemoglobin Abruzzo with HbS: first family study from Central India. Int J Lab Hematol. 2016 Apr;38(2):e30-4. Venkateswaran L et al. Homozygous hemoglobin Abruzzo in a North American child. J Pediatr Hematol Oncol. 2005 Nov;27(11):618-20. Wajcman H and Galacteros F. Hemoglobins with high oxygen affinity leading to erythrocytosis. New variants and new concepts. Hemoglobin. 2005;29(2):91-106. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 18, 2020	The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

HEMOGLOBIN ABRUZZO 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	Benign	0.24
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.096	T;T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Uncertain	0.53
Sift	Uncertain	0.014	D;.
Sift4G	Benign	1.0	T;.
Polyphen		0.0040	B;B
Vest4		0.82
MutPred		0.64		Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);
MVP		0.89
MPC		0.038
ClinPred		0.15	T
GERP RS		4.7
Varity_R		0.53
gMVP		0.73

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: rs33918338; hg19: chr11-5246841; COSMIC: COSV100092531; COSMIC: COSV100092531;