rs63750158

Variant names:

• chr16-173008-G-A
• rs63750158
• ENST00000482565.1:n.115G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-173008-G-A
• chr16-173008-G-C
• chr16-173008-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The ENST00000482565.1(HBA2):​n.115G>A variant causes a non coding transcript exon change. In-silico tool predicts a pathogenic outcome for this variant. 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 ENST00000482565.1 non_coding_transcript_exon
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.07
• Publications: 1 publications found

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

ENSG00000294455 (HGNC:):

ACMG classification

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 16-173008-G-A is Pathogenic according to our data. Variant chr16-173008-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 439126.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	c.95+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.95+1G>A		splice_donor_variant, intron_variant	Intron 1 of 2	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD2 exomes AF: 0.0000181 AC: 1 AN: 55352 AF XY: 0.0000358

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: 0.0000487

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000902 AC: 4 AN: 443356 Hom.: 1 Cov.: 0 AF XY: 0.0000171 AC XY: 4 AN XY: 233618

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11132

American (AMR) AF: 0.00 AC: 0 AN: 21020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13814

East Asian (EAS) AF: 0.00 AC: 0 AN: 30330

South Asian (SAS) AF: 0.0000653 AC: 3 AN: 45974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28882

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1820

European-Non Finnish (NFE) AF: 0.00000377 AC: 1 AN: 265068

Other (OTH) AF: 0.00 AC: 0 AN: 25316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Dec 20, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 29, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jul 13, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.1
GERP RS		3.9
PromoterAI		0.015	Neutral
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs63750158; hg19: chr16-223007;