chr11-5226787-GACC-G

Position:

• chr11-5226787-GACC-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The NM_000518.5(HBB):​c.102_104delGGT​(p.Val35del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 6.93

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000518.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-5226787-GACC-G is Pathogenic according to our data. Variant chr11-5226787-GACC-G is described in ClinVar as [Pathogenic]. Clinvar id is 15532.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-5226787-GACC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBB	NM_000518.5	c.102_104delGGT	p.Val35del	disruptive_inframe_deletion	2/3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.102_104delGGT	p.Val35del	disruptive_inframe_deletion	2/3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 06, 2021

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mutiple HBB-related blood conditions (OMIM). Dominant negative is also a suggested mechanism (PMID: 29700171). (I) 0108 - This gene is associated with both recessive and dominant disease. Variants in this gene have been reported in patients with autosomal recessive sickle cell anemia (MIM#603903), and autosomal dominant delta-beta thalassemia (MIM#141749), Heinz body anemia (MIM#140700) and hereditary persistence of fetal hemoglobin (MIM#141749) (OMIM, PMID: 20301599). Beta thalassemia (MIM#613985) has been associated with both dominant and recessive disease(PMID: 20301599, PMID: 1911355). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable clinical severity is dependent on whether variants in HBB are heterozygous, homozygous or compound heterozygous, and the amount of residual protein that is expressed (PMID: 20301599). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0601 - Variant is located at the well-established interface residue within the haemoglobin beta-like domain, and has been functionally proven to result in a defective protein when altered (NCBI, PMID: 12603091, PMID: 12908805). (SP) 0702 - Other missense variants at this same protein position have strong previous evidence for pathogenicity. These missense variants (p.Val35Phe, p.Val35Asp, p.Val35Leu) have been reported multiple times in patients with erythrocytosis, haemolytic anaemia and haemoglobinopathy. The variants were de novo in two of these patients, and are commonly reported using older nomenclature where this amino acid was at position 34 (ClinVar, OMIM, PMID: 12603091, PMID: 12908805, PMID: 26635043). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in a single individual. This variant has been reported in a single de novo patient with beta thalassaemia, and is referred to as the Korean variant (PMID: 1911355). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

HEMOGLOBIN KOREA Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35699671; hg19: chr11-5248017;