NM_000517.6(HBA2):c.60del (p.His21fs) AND alpha Thalassemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 3, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001275677.3

Allele description [Variation Report for NM_000517.6(HBA2):c.60del (p.His21fs)]

NM_000517.6(HBA2):c.60del (p.His21fs)

Genes:

LOC106804612:hemoglobin subunit alpha 2 recombination region [Gene]
HBA2:hemoglobin subunit alpha 2 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

16p13.3

Genomic location:

Preferred name:

NM_000517.6(HBA2):c.60del (p.His21fs)

HGVS:

NC_000016.10:g.172972del
NG_000006.1:g.33835del
NG_046165.1:g.2711del
NG_059186.1:g.1322del
NG_059271.1:g.5126del
NM_000517.6:c.60delMANE SELECT
NP_000508.1:p.His21fs
LRG_1240t1:c.60del
LRG_1225:g.1322del
LRG_1240:g.5126del
LRG_1240p1:p.His21fs
NC_000016.10:g.172972delG
NC_000016.9:g.222971del
NM_000517.4:c.60delG
NM_000517.6:c.60delGMANE SELECT
p.His21Thrfs*29

Protein change:

H21fs

Links:

dbSNP: rs886041399

NCBI 1000 Genomes Browser:

rs886041399

Molecular consequence:

NM_000517.6:c.60del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: alpha Thalassemia
Synonyms:: A-Thalassemia; Alpha thalassemia spectrum
Identifiers:: MONDO: MONDO:0011399; MedGen: C0002312; Orphanet: 846; OMIM: 604131

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001461035	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004848828	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001461035

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV004848828

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 3, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Natera, Inc., SCV001461035.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848828.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The p.His21ThrfsX29 variant in the HBA2 has been reported in several individuals with alpha thalassemia,both in the homozygous state or in th ecompound heterozygous state in trans with another pathogenic variant (Harteveld 2003 PMID: 14508795, Keikhaei 2018 PMID: 29627922). It has also been reported in ClinVar (Variation ID 280127) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 21 and leads to a premature termination codon 29 amino acids downstream. Loss of function of the HBA2 gene is an established disease mechanism in autosomal recessive alpha Thalassaemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_Strong.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

ClinVar

Relating variation to medicine