rs41457746

Positions:

chr16-173123-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000517.6(HBA2):c.96-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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
NM_000517.6 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

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

Conservation

PhyloP100: 8.62

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 links:

HBA2 (HGNC:):

HBA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.4, offset of 28, new splice context is: tgtccttccccaccaccaAGacc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 16-173123-A-G is Pathogenic according to our data. Variant chr16-173123-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 15679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-173123-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.96-2A>G		splice_acceptor_variant, intron_variant		ENST00000251595.11	NP_000508.1	P69905D1MGQ2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HBA2	ENST00000251595.11 linkuse as main transcript	c.96-2A>G	splice_acceptor_variant, intron_variant		1	NM_000517.6	ENSP00000251595.6	P69905
HBA2	ENST00000484216.1 linkuse as main transcript	c.63-2A>G	splice_acceptor_variant, intron_variant		1		ENSP00000495899.1	A0A2R8Y7C0
HBA2	ENST00000482565.1 linkuse as main transcript	n.230A>G	non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.-1-2A>G	splice_acceptor_variant, intron_variant		2		ENSP00000380908.1	G3V1N2

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

GnomAD4 exome

AF:

0.0000409

AC:

AN:

562962

Hom.:

Cov.:

AF XY:

0.0000539

AC XY:

AN XY:

297030

show subpopulations

Gnomad4 AFR exome

AF:

0.0000700

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000573

Gnomad4 OTH exome

AF:

0.0000670

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000595

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 28, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 05, 2021

- -

Alpha-thalassemia, Dutch type

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.90

GERP RS

4.2

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over