chr11-5226626-A-G

Position:

• chr11-5226626-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000518.5(HBB):​c.266T>C​(p.Leu89Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L89R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 8.51

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]

HBB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-5226626-A-G is Pathogenic according to our data. Variant chr11-5226626-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15343.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.266T>C	p.Leu89Pro	missense_variant	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.266T>C	p.Leu89Pro	missense_variant	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 01, 2017	The Hb Santa Ana variant (HBB: c.266T>C; Leu88Pro) (rs33940204) has been reported in a heterozygous state in multiple individuals with hemolytic anemia, jaundice and splenomegaly (Fairbanks 1969, Opfell 1968, HbVar database and references therein). It has also been reported as a de-novo alteration in an affected individual, which co-segregated with clinical symptoms in the subsequent generation (Opfell 1968). Functional characterization of the variant hemoglobin indicates reduced stability and increased formation of inclusion bodies, while tetramers containing the variant hemoglobin are bound to two heme groups instead of four (Opfell 1968). Another missense variant at this position, Leu88Arg, has also been implicated as an unstable hemoglobin resulting in similar clinical symptoms when found in a heterozygous state (Hollender 1969). The Leu88Pro variant is listed in ClinVar (Variation ID: 15343), but is not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The leucine at position 88 is highly conserved (Alamut v2.10), and is located in the heme-binding pocket of the protein (Hollender 1969, Opfell 1968). Computational algorithms (Align GVGD, Mutation Taster, PolyPhen-2, SIFT) predict that the Leu88Pro variant has an impact on HBB protein structure or function. Based on the above information, the Hb Santa Ana variant is classified as pathogenic. References: Link to HbVar database for Hb Santa Ana: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=420 Fairbanks V et al. Three families with unstable hemoglobinopathies (Köln, Olmsted and Santa Ana) causing hemolytic anemia with inclusion bodies and pigmenturia. Am J Med. 1969; 46(3):344-59. Hollender A et al. New unstable haemoglobin borås: beta 88 (F4) leucine-arginine. Nature. 1969; 222(5197):953-5. Opfell R et al. Hereditary non-spherocytic haemolytic anaemia with post-splenectomy inclusion bodies and pigmenturia caused by an unstable haemoglobin Santa Ana-beta-88 (F4) leucine--proline. J Med Genet. 1968; 5(4):292-7. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Sep 27, 2022

ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM6 moderated, PP3 supporting -

HEMOGLOBIN SANTA ANA 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;.;T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;D;D;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.7	D;.;.;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0050	D;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;.
Polyphen		1.0	D;D;.;.
Vest4		1.0
MutPred		0.92		Gain of disorder (P = 0.0497);Gain of disorder (P = 0.0497);Gain of disorder (P = 0.0497);Gain of disorder (P = 0.0497);
MVP		0.94
MPC		0.27
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.96
gMVP		1.0

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: rs33940204; hg19: chr11-5247856;