rs41474145

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PP3PP5_Very_Strong

The ENST00000482565.1(HBA2):n.116_120delTGAGG variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 3)

Exomes 𝑓: 0.00029 ( 10 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
ENST00000482565.1 non_coding_transcript_exon

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 9.03

Publications

4 publications found

Variant links:

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

HBA2 Gene-Disease associations (from GenCC):

alpha thalassemia spectrum
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
erythrocytosis, familial, 7
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hemoglobin M disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hb Bart's hydrops fetalis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hemoglobin H disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Heinz body anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
methemoglobinemia, alpha type
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

HBA2 links:

ENSG00000294455 (HGNC:):

ENSG00000294455 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 16-173004-AGAGGT-A is Pathogenic according to our data. Variant chr16-173004-AGAGGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 375746.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
HBA2	NM_000517.6 link	c.95+2_95+6delTGAGG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 2	ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11 link	c.95+2_95+6delTGAGG		splice_donor_variant, splice_region_variant, intron_variant	Intron 1 of 2	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

9452

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00549

GnomAD2 exomes

AF:

0.000294

AC:

AN:

54504

AF XY:

0.000255

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000817

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000147

Gnomad OTH exome

AF:

0.00155

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000292

AC:

128

AN:

439000

Hom.:

AF XY:

0.000290

AC XY:

AN XY:

231172

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

10946

American (AMR)

AF:

0.000693

AC:

AN:

20196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13572

East Asian (EAS)

AF:

0.00

AC:

AN:

30114

South Asian (SAS)

AF:

0.000617

AC:

AN:

45406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28718

Middle Eastern (MID)

AF:

0.0182

AC:

AN:

1872

European-Non Finnish (NFE)

AF:

0.000167

AC:

AN:

263062

Other (OTH)

AF:

0.000319

AC:

AN:

25114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000106

AC:

AN:

9420

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

4366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

1348

American (AMR)

AF:

0.00

AC:

AN:

1398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

238

East Asian (EAS)

AF:

0.00

AC:

AN:

946

South Asian (SAS)

AF:

0.00

AC:

AN:

736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

4120

Other (OTH)

AF:

0.00549

AC:

AN:

182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.825

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.0000793

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

alpha Thalassemia

Pathogenic:4Other:1

Oct 19, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000375746 /PMID: 6946451). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Aug 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 05, 2022

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.95+2_95+6del variant is classified as Pathogenic (PVS1, PS4, PP4) The HBA2 c.95+2_95+6del variant is located in a splice donor region. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). This pentanucleotide HBA2:c.95+2_95+6delTGAGG deletion occurs within the 5' splice junction of the first intervening sequence, preventing normal RNA splicing. This mutation is listed on the Haemoglobin Variant Database as an alpha thalassaemia mutation (PMID: 7151175) (PS4). Present in numerous internal database patients as per alamut with consistent symptoms of alpha thalassaemia carrier. No functional studies performed. The clinical features of this case are highly specific for HBA1/2, and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4). Variants in HBA1/2 are highly specific for alpha thalassaemia. The variant has been reported in dbSNP (rs41474145) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 375746). It has been reported in HGMD (CD810004). -

Feb 10, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.95+2_95+6del variant in HBA2 is a common pathogenic variant for alpha thalassemia in the Mediterranean region (Felber 1982 PMID: 7151175, Lacerra 2004 PMID: 15365991, Orkin 1981 PMID: 6946451, HbVar database: https://globin.bx.psu.edu/hbvar/menu.html; HbVarID:1065). This variant has been reported by other clinical laboratories in ClinVar (Variation ID 375746) and was absent from large population studies (gnomAD, v.3.1.2). This deletion affects the canonical splice site position (+2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Biallelic loss of function of the HBA2 gene is an established disease mechanism in autosomal recessive alpha thalassemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive alpha thalassemia. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong, PM2_supporting. -

not provided

Pathogenic:4

Dec 09, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.95+2_95+6del variant (also known as c.95+2_95+6delTGAGG and IVS1 (-5nt)) disrupts a canonical splice-donor site and interferes with normal HBA2 mRNA splicing (PMIDs: 6946451 (1981), 7151175 (1982), 20507641 (2010)). This variant has been reported in the published literature in multiple individuals including homozygous and compound heterozygous cases who were affected with alpha thalassemia or related conditions (PMIDs: 6946451 (1981), 7151175 (1982), 15365991 (2004), 29115104 (2018), 32893703 (2020), 38708170 (2024)). An in vitro study showed that no functional protein was synthesized from the mutant alpha2-globin allele (PMID: 7151175 (1982)). The frequency of this variant in the general population, 0.00082 (9/11036 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The HBA2 c.95+2_95+6del variant (rs41474145, HbVar ID: 1065, also known as alpha-thal-2 (-5nt) and IVS1 (-5nt)) is a common pathogenic alpha thalassemia variant and has been reported in heterozygous individuals with mild hypochromic microcytic anemia or silent carriers and in compound heterozygous individuals with alpha-thalassemia trait (Alhuthali 2023, Lacerra 2004, Orkin 1981, see HbVar link). This variant disrupts the canonical splice donor site of intron 1 and alters splicing (Felber 1982, Orkin 1981). Based on the information available, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alhuthali HM et al. Molecular patterns of alpha-thalassemia in the kingdom of Saudi Arabia: identification of prevalent genotypes and regions with high incidence. Thromb J. 2023 Nov 10;21(1):115. PMID: 37950286. Felber BK et al. Abnormal RNA splicing causes one form of alpha thalassemia. Cell. 1982 Jul;29(3):895-902. PMID: 7151175. Lacerra G et al. Sequence variations of the alpha-globin genes: scanning of high CG content genes with DHPLC and DG-DGGE. Hum Mutat. 2004 Oct;24(4):338-49. PMID: 15365991. Orkin SH et al. Mutation in an intervening sequence splice junction in man. Proc Natl Acad Sci U S A. 1981 Aug;78(8):5041-5. PMID: 6946451. -

Apr 18, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Common variant reported in individuals of Mediterranean ethnicity with HbH disease (Orkin et al., 1981; Mesbah-Amroun et al., 2008; Farra et al., 2014; de la Fuent-Gonzalo et al., 2019); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Also denoted as IVS1-5nt and alpha-Hph due to alternative nomenclature; This variant is associated with the following publications: (PMID: 6946451, 15365991, 26771086, 31025160, 7151175, 25284125, 18473243, 23215864, 31589614, 29627922) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7

Pathogenic:1

Feb 24, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.0

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over