16-173208-G-A

Variant names:

• chr16-173208-G-A
• rs281864846
• NM_000517.6:c.179G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM5 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. G60R) has been classified as Likely pathogenic.

• 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:5 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

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 8 uncertain in NM_000517.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-173207-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.179G>A	p.Gly60Asp	missense_variant	Exon 2 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.179G>A	p.Gly60Asp	missense_variant	Exon 2 of 3	1	NM_000517.6	ENSP00000251595.6
HBA2	ENST00000484216.1	c.146G>A	p.Gly49Asp	missense_variant	Exon 2 of 2	1		ENSP00000495899.1
HBA2	ENST00000482565.1	n.315G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
HBA2	ENST00000397806.1	c.83G>A	p.Gly28Asp	missense_variant	Exon 2 of 3	2		ENSP00000380908.1

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 AC: 0 AN: 20238

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35662

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 22770

Gnomad4 EAS exome AF: 0.0000292 AC: 1 AN: 34242

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 70816

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 34088

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 758436

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 45334

GnomAD4 genome Cov.: 18

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 09, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 03, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a common pathogenic variant among individuals of Southeast Asian background (PMID: 36900038); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(G59D) and Hb Adana; This variant is associated with the following publications: (PMID: 30025477, 29749692, 30205726, 8237999, 31286593, 26351923, 37236975, 9029003, 38112059, 27173219, 30663218, 11722414, 20642338, 24829075, 27271331, 30623696, 32860378, 33364739, 24351118, 36900038, 38694420) -

alpha Thalassemia Pathogenic:1

Jul 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 10, 2020

Genomic Medicine Lab, University of California San Francisco

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HEMOGLOBIN H HYDROPS FETALIS SYNDROME Other:1

Sep 12, 2022

OMIM

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	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
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
Mutation Taster		=9/91	disease causing (ClinVar)

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;