rs41457746

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_StrongPP5_Very_Strong

The ENST00000482565.1(HBA2):n.230A>G variant causes a non coding transcript exon change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 9)

Exomes 𝑓: 0.000041 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
ENST00000482565.1 non_coding_transcript_exon

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.62

Publications

1 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: Pathogenic. The variant received 12 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-173123-A-G is Pathogenic according to our data. Variant chr16-173123-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 15679.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.96-2A>G		splice_acceptor_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.96-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 2	1	NM_000517.6	ENSP00000251595.6		P69905

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

60196

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:

0.0000595

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000104

AC:

AN:

96206

AF XY:

0.0000200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000409

AC:

AN:

562962

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

297030

show subpopulations

African (AFR)

AF:

0.0000700

AC:

AN:

14278

American (AMR)

AF:

0.00

AC:

AN:

33034

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17258

East Asian (EAS)

AF:

0.00

AC:

AN:

31228

South Asian (SAS)

AF:

0.00

AC:

AN:

56216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2284

European-Non Finnish (NFE)

AF:

0.0000573

AC:

AN:

348964

Other (OTH)

AF:

0.0000670

AC:

AN:

29858

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000332

AC:

AN:

60196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

27086

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

9464

American (AMR)

AF:

0.00

AC:

AN:

6126

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1826

East Asian (EAS)

AF:

0.00

AC:

AN:

2444

South Asian (SAS)

AF:

0.00

AC:

AN:

1284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000595

AC:

AN:

33632

Other (OTH)

AF:

0.00

AC:

AN:

784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 03, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The IVS-I-116 variant (HBA2: c.96-2A>G, HbVar ID: 1066, rs41457746) is reported in the literature in multiple individuals affected with alpha (+) thalassemia in the heterozygous state (see HbVar and references therein, Bayat 2013). This variant was observed in trans with the alpha 3.7 deletion in an individual with alpha thalassemia with Hb H inclusion bodies (Harteveld 2003). Additionally, this variant was detected in a fetus with Hb H disease in trans with the Southeast Asian deletion (--SEA) (He 2018). This variant is also reported in ClinVar (Variation ID: 15679). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice acceptor site of intron one, which is likely to negatively impact gene function. Analyses of the variant transcript show intron one is retained leading to a premature stop codon and post-transcriptional instability (Harteveld 1996). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/menu.html Bayat N et al. Novel mutations responsible for alpha-thalassemia in Iranian families. Hemoglobin. 2013;37(2):148-59. PMID: 23402770. Harteveld CL et al. An IVS1-116 (A-->G) acceptor splice site mutation in the alpha 2 globin gene causing alpha + thalassaemia in two Dutch families. Br J Haematol. 1996 Dec;95(3):461-6. PMID: 8943885. Harteveld CL et al. The Dutch IVS-I-116 (A --> G) (alpha2) thalassemia mutation induces Hb H inclusion bodies when found in combination with the -alpha3.7 deletion defect. Hemoglobin. 2003 Feb;27(1):49-51. PMID: 12603095. He XH et al. First Report of a Case with Nondeletional Hb H Disease Caused by IVS-I-116 (A>G) of the alpha2-Globin Gene. Hemoglobin. 2018 Sep-Nov;42(5-6):344-346. PMID: 30676123. -

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

Pathogenic:1

Nov 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Alpha-thalassemia, Dutch type

Pathogenic:1

Feb 01, 2003

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.90

PhyloP100

8.6

GERP RS

4.2

PromoterAI

-0.070

Neutral

(source)

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.68

Position offset: 30

DS_AL_spliceai

1.0

Position offset: 2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over