rs281864846

Positions:

• chr16-173208-G-A
• chr16-173208-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000517.6(HBA2):​c.179G>A​(p.Gly60Asp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 18)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.26

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-173208-G-A is Pathogenic according to our data. Variant chr16-173208-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 439112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HBA2	NM_000517.6	c.179G>A	p.Gly60Asp	missense_variant	2/3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.179G>A	p.Gly60Asp	missense_variant	2/3	1	NM_000517.6	ENSP00000251595	P1
HBA2	ENST00000484216.1	c.149G>A	p.Gly50Asp	missense_variant	2/2	1		ENSP00000495899
HBA2	ENST00000482565.1	n.315G>A		non_coding_transcript_exon_variant	1/2	1
HBA2	ENST00000397806.1	c.83G>A	p.Gly28Asp	missense_variant	2/3	2		ENSP00000380908

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome AF: 9.76e-7 AC: 1 AN: 1024858 Hom.: 0 Cov.: 14 AF XY: 0.00000192 AC XY: 1 AN XY: 519910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000292

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 18

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The Hb Adana variant (HBA2: c.179G>A; p.Gly60Asp, also known as Gly59Asp when numbered from the mature protein, rs281864846, HbVar ID: 87) is reported in the literature in multiple individuals with alpha-thalassemia, Hb H disease, and hydrops fetalis usually in combination with other pathogenic variants and is often associated with a severe course of disease (see HbVar and references therein, Alauddin 2014 and 2018, Megawati 2014, Nainggolan 2010, Singh 2018). This variant is reported as highly unstable (see HbVar). This variant is reported in ClinVar (Variation ID: 439112) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.867). Based on available information, this variant is considered to be pathogenic. References: Link to HbVar database: https://globin.bx.psu.edu/hbvar/menu.html Alauddin H et al. A case series of a-thalassemia intermedia due to compound heterozygosity for Hb Adana (HBA2: c179G>A (or HBA1); p.Gly60Asp) with other alpha-thalassemias in Malay families. Hemoglobin. 2014;38(4):277-81. PMID: 24829075. Alauddin H et al. A Unique Interaction of IVS-I-1 (G>A) (HBA2: c.95+1G>A) with Hb Adana (HBA2: c.179G>A) Presenting as Transfusion-Dependent alpha-Thalassemia. Hemoglobin. 2018 Jul;42(4):247-251. PMID: 30623696. Megawati D et al. Severe alpha-thalassemia intermedia due to a compound heterozygosity for the highly unstable Hb Adana (HBA2: c.179G>A) and a novel codon 24 (HBA2: c.75T>A) mutation. Hemoglobin. 2014;38(2):149-51. PMID: 24351118. Nainggolan IM et al. Hydrops fetalis associated with homozygosity for Hb Adana (alpha59(E8)Gly-->Asp (alpha2)). Hemoglobin. 2010;34(4):394-401. PMID: 20642338. Singh SA et al. Hb Adana (HBA2 or HBA1: c.179G > A) and alpha thalassemia: Genotype-phenotype correlation. Pediatr Blood Cancer. 2018 Sep;65(9):e27220. PMID: 29749692. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2023	The variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant protein is described as being unstable and as having a range of mild to severe presentations of alpha thalassemia in multiple individuals with different deletional and non-deletional pathogenic variants (PMIDs: 9029003 (1997), 20642338 (2010), 27271331 (2016), 29749692 (2018), 33364739 (2020)). Based on the available information, this variant is classified as pathogenic. -

alpha Thalassemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 21, 2023

Variant summary: HBA2 c.179G>A (p.Gly60Asp) (also known as Gly59Asp/ Hb Adana ) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 131276 control chromosomes (gnomAD). c.179G>A has been reported in the literature in multiple individuals affected with alpha-thalassemia and hydrops fetalis (examples:Curuk_1993, Nainggolan_2010, Megawati_2014, and Alauddin_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 8237999, 20642338, 24351118, 24829075). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Non-immune hydrops fetalis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genomic Medicine Lab, University of California San Francisco

Dec 10, 2020

- -

HEMOGLOBIN H HYDROPS FETALIS SYNDROME Other:1

other, no assertion criteria provided

literature only

OMIM

Sep 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.5	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.67
MutPred		0.99		Gain of ubiquitination at K62 (P = 0.0525);.;
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		3.2
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs281864846; hg19: chr16-223207;