rs63750158

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_StrongPP3_StrongPP5_Very_Strong

The NM_000517.6(HBA2):c.95+1G>A variant causes a splice donor change. 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: not found (cov: 3)

Exomes 𝑓: 0.0000090 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

HBA2
NM_000517.6 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.07

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:

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, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.3053613 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.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-173008-G-A is Pathogenic according to our data. Variant chr16-173008-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 439126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBA2	NM_000517.6 linkuse as main transcript	c.95+1G>A		splice_donor_variant		ENST00000251595.11

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris
HBA2	ENST00000251595.11 linkuse as main transcript	c.95+1G>A	splice_donor_variant		1	NM_000517.6	P1
HBA2	ENST00000484216.1 linkuse as main transcript	c.64+1G>A	splice_donor_variant		1
HBA2	ENST00000482565.1 linkuse as main transcript	n.115G>A	non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1 linkuse as main transcript	c.-2+50G>A	intron_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000181

AC:

AN:

55352

Hom.:

AF XY:

0.0000358

AC XY:

AN XY:

27898

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000487

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000902

AC:

AN:

443356

Hom.:

Cov.:

AF XY:

0.0000171

AC XY:

AN XY:

233618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000653

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000377

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 20, 2018

The HBA2 c.95+1G>A variant (rs63750158) is reported in the literature in a sickle cell carrier with microcytic anemia and reduced Hb S levels (Waye 2009). An analogous c.95+1G>A variant in the HBA1 gene has also been reported in several individuals with Hb H disease that also carried the --SEA deletion (Harteveld 2000, Viprakasit 2014). The HBA2 c.95+1G>A variant is reported in ClinVar (Variation ID: 439126), and it is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 1, and RNA studies indicate this leads to splicing at a cryptic splice donor, deletion of 49 nucleotides, and introduction of a premature stop codon (Harteveld 2000, Qadah 2014). Based on available information, this variant is considered to be pathogenic. References: Harteveld CL et al. alpha-thalassaemia as a result of a novel splice donor site mutation of the alpha1-globin gene. Br J Haematol. 2000 Sep;110(3):694-8. Qadah T et al. In vitro characterization of the a-thalassemia point mutation HBA2:c.95+1G>A [IVS-I-1(G>A) (a2)]. Hemoglobin. 2012;36(1):38-46. Viprakasit V et al. Clinical presentation and molecular identification of four uncommon alpha globin variants in Thailand. Initiation codon mutation of a2-globin Gene (HBA2:c.1delA), donor splice site mutation of a1-globin gene (IVSI-1, HBA1:c.95 + 1G>A), hemoglobin Queens Park/Chao Pra Ya (HBA1:c.98T>A) and hemoglobin Westmead (HBA2:c.369C>G). Acta Haematol. 2014;131(2):88-94. Waye JS et al. alpha-Thalassemia caused by two novel splice mutations of the alpha2-globin gene: IVS-I-1 (G>A and G>T). Hemoglobin. 2009;33(6):519-22. -

alpha Thalassemia

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 29, 2017

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 13, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D

GERP RS

3.9

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: -50

DS_DL_spliceai

0.99

Position offset: -1

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