rs63750928

chr11-5226997-TCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000518.5(HBB):c.22_24del(p.Glu8del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E8E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HBB NM_000518.5 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.13

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 13 uncertain in NM_000518.5
• 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 11-5226997-TCTC-T is Pathogenic according to our data. Variant chr11-5226997-TCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.22_24del	p.Glu8del	inframe_deletion	1/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.22_24del	p.Glu8del	inframe_deletion	1/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1460294 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726598

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2021	The Hb Leiden variant (HBB: c.22_24del; p.Glu8del, also known as Glu7del when numbered from the mature protein, rs63750928) is reported in the literature in multiple individuals affected with episodes of hemolytic anemia, although most exhibited normal hematology outside of hemolytic episodes (De Jong 1968, Rieder 1974, Schroeder 1982, HbVar database and references therein). Additionally, this variant has been observed in trans to HbE in a proband with a clinical picture of mild thalassemia intermedia and was absent from both parents, suggesting a de novo origin in this individual (Sanguansermsri 2003). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant deletes a single glutamate residue, leaving the rest of the protein in-frame. Functional analyses suggest the variant is mildly unstable, although it is unclear if this is clinically significant (Rieder 1974). Still, based on available information, including its occurrence in multiple affected individuals, the Hb Leiden variant is considered to be likely pathogenic. References: HbVar link for Hb Leiden: http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=720 De Jong WW et al. Haemoglobin Leiden: deletion of beta-6 or 7 glutamic acid. Nature. 1968 Nov 23;220(5169):788-90. PMID: 5698750 Rieder RF and James GW. Imbalance in alpha and beta globin synthesis associated with a hemoglobinopathy. J Clin Invest. 1974 Oct;54(4):948-56. PMID: 4430724. Sanguansermsri P et al. Spontaneous mutation of the hemoglobin Leiden (beta 6 or 7 Glu-->0) in a Thai girl. Haematologica. 2003 Dec;88(12):ECR35. PMID: 14688008. Schroeder WA et al. An unusual phenotypic expression of Hb-Leiden. Biochem Genet. 1982 Dec;20(11-12):1175-87. PMID: 7165693. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2021	This variant has been reported to be an unstable hemoglobin variant with slightly increased oxygen affinity. Heterozygosity for Hb Leiden is associated with mild hemolytic anemia and reticulocytosis (PMID 6874375 (1983), 14688008 (2003)). -

HEMOGLOBIN LEIDEN Other:1

other, no assertion criteria provided

literature only

OMIM

Nov 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs63750928; hg19: chr11-5248227;