rs41474145

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1_StrongPS3PP5_Very_Strong

The NM_000517.6(HBA2):c.95+2_95+6delTGAGG variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002047269: An in vitro study showed that no functional protein was synthesized from the mutant alpha2-globin allele (PMID:7151175 (1982)).".

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 3)

Exomes 𝑓: 0.00029 ( 10 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 splice_donor, splice_region, intron

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, ClinGen, 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
unstable hemoglobin disease
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: Pathogenic. The variant received 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.30769232 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.8, offset of -19, new splice context is: atgGTgcgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV002047269: An in vitro study showed that no functional protein was synthesized from the mutant alpha2-globin allele (PMID: 7151175 (1982)).

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000517.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HBA2	NM_000517.6	MANE Select	c.95+2_95+6delTGAGG		splice_donor splice_region intron	N/A	NP_000508.1	D1MGQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HBA2	ENST00000251595.11	TSL:1 MANE Select	c.95+2_95+6delTGAGG	splice_donor splice_region intron	N/A	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1	TSL:1	c.62+2_62+6delTGAGG	splice_donor splice_region intron	N/A	ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1	TSL:1	n.116_120delTGAGG	non_coding_transcript_exon	Exon 1 of 2

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

alpha Thalassemia (5)

not provided (4)

alpha Thalassemia;C0700299:Heinz body anemia;C3161174:Hemoglobin H disease;C4693823:Erythrocytosis, familial, 7 (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over