rs33969853

Variant names:

• chr11-5226674-C-CT
• rs33969853
• NM_000518.5:c.217dupA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000518.5(HBB):​c.217dupA​(p.Ser73LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HBB NM_000518.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 0.303

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 82 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-5226674-C-CT is Pathogenic according to our data. Variant chr11-5226674-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBB	NM_000518.5	c.217dupA	p.Ser73LysfsTer2	frameshift_variant	Exon 2 of 3	ENST00000335295.4	NP_000509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBB	ENST00000335295.4	c.217dupA	p.Ser73LysfsTer2	frameshift_variant	Exon 2 of 3	1	NM_000518.5	ENSP00000333994.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251430 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

beta Thalassemia Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is classified as likely pathogenic in the context of Hb beta chain-related hemoglobinopathy. Please note that S73Kfs*2 is associated with beta thalassemia and is classified as a beta-zero variant. Sources cited for classification include the following: PMID 6585831. Classification of NM_000518.4(HBB):c.217dupA(aka p.S73Kfs*2) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is observed in an individual with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, no assertion criteria provided	curation	The ITHANET community portal, The Cyprus Institute of Neurology and Genetics	Nov 25, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 15, 2016	Variant summary: The HBB c.217dupA (p.Ser73Lysfs) variant results in a premature termination codon, predicted to cause a truncated or absent HBB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Gly84fs). One in silico tool predicts a damaging outcome for this variant. Additionally, Cheng_PNAS_1984 reported the absence of beta-globin RNA in erythroid cells of a patient homozygous for this variant. The variant was reported in multiple unrelated BTHAL patients in the literature, and authors all classified the variant as pathogenic. This variant was found in 1/121394 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic HBB variant (0.0111803). Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2024	The HBB c.217dupA; p.Ser73LysfsTer2 variant (also known as Ser72fs when numbered from the mature protein or as codon 71/72 (+A); HbVar ID: 869) has been reported in individuals with beta(0) thalassemia, including in a homozygous individual with no detectable HBB mRNA (see HbVar, Cheng 1984). This variant is found on only two chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the c.217dupA variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Cheng T et al. beta-Thalassemia in Chinese: use of in vivo RNA analysis and oligonucleotide hybridization in systematic characterization of molecular defects. Proc Natl Acad Sci U S A. 1984; 81(9):2821-5. PMID: 6585831. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Ser73Lysfs*2) in the HBB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HBB are known to be pathogenic (PMID: 23637309). This variant is present in population databases (rs606231217, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive beta thalassemia (PMID: 6585831). This variant is also known as c.216_217insA or as an insertion of an A nucleotide between codons 71 and 72. ClinVar contains an entry for this variant (Variation ID: 15419). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 30, 2020	The HBB c.217dup (p.Ser73Lysfs*2) pathogenic variant alters the translational reading frame of the HBB mRNA and causes the premature termination of HBB protein synthesis. This variant has been reported to be associated with beta(0)-thalassemia (PMIDs: 26956563 (2016), 24369358 (2014), 6585831 (1984)). -

Beta zero thalassemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1984

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2016

The c.217dupA pathogenic mutation (also known as codons 71/72 insertion A), located in coding exon 2 of the HBB gene, results from a duplication of A at nucleotide position 217, causing a translational frameshift with a predicted alternate stop codon (p.S73Kfs*2). This variant was identified previously in a homozygous individual with beta-thalassemia (Cheng TC et al. Proc. Natl. Acad. Sci. U.S.A., 1984 May;81:2821-5). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

-

PM2_Supporting+PVS1+PS4+PP4 -

Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:METHEMOGLOBINEMIA, BETA TYPE;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 03, 2024

- -

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: rs33969853; hg19: chr11-5247904;